Protein Tyrosine Phosphatase 2 (SHP-2) Moderates Signaling by gp130 but Is Not Required for the Induction of Acute-Phase Plasma Protein Genes in Hepatic Cells
Open accessAbstract
Signals propagated via the gp130 subunit of the interleukin-6 (IL-6)-type cytokine receptors mediate, among various cellular responses, proliferation of hematopoietic cells and induction of acute-phase plasma protein (APP) genes in hepatic cells. Hematopoietic growth control by gp130 is critically dependent on activation of both STAT3 and protein tyrosine phosphatase 2 (SHP-2). To investigate whether induction of APP genes has a similar requirement for SHP-2, we constructed two chimeric receptors, G-gp130 and G-gp130(Y2F), consisting of the transmembrane and cytoplasmic domains of gp130 harboring either a wild-type or a mutated SHP-2 binding site, respectively, fused to the extracellular domain of the granulocyte colony-stimulating factor (G-CSF) receptor. Rat hepatoma H-35 cells stably expressing the chimeric receptors were generated by retroviral transduction. Both chimeric receptors transmitted a G-CSF-induced signal characteristic of that triggered by IL-6 through the endogenous gp130 receptor; i.e., both activated the appropriate JAK, induced DNA binding activity by STAT1 and STAT3, and up-regulated expression of the target APP genes, those for alpha-fibrinogen and haptoglobin. Notwithstanding these similarities in the patterns of signaling responses elicited, mutation of the SHP-2 interaction site in G-gp130(Y2F) abrogated ligand-activated receptor recruitment of SHP-2 as expected. Moreover, the tyrosine phosphorylation state of the chimeric receptor, the associated JAK activity, and the induced DNA binding activity of STAT1 and STAT3 were maintained at elevated levels and for an extended period of time in G-gp130(Y2F)-expressing cells following G-CSF treatment compared to that in cells displaying the G-gp130 receptor. H-35 cells ectopically expressing G-gp130(Y2F) were also found to display an enhanced sensitivity to G-CSF and a higher level of induction of APP genes. Overexpression of the enzymatically inactive SHP-2 enhanced the signaling by the wild-type but not by the Y2F mutant G-gp130 receptor. These results indicate that gp130 signaling for APP gene induction in hepatic cells differs qualitatively from that controlling the proliferative response in hematopoietic cells in not being strictly dependent on SHP-2. The data further suggest that SHP-2 functions normally to attenuate gp130-mediated signaling in hepatic (and, perhaps, other) cells by moderating JAK action.
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Written from the paper’s full text.
TL;DR
In rat hepatoma cells, gp130-mediated induction of acute-phase plasma protein (APP) genes does not require SHP-2 recruitment; instead, SHP-2 binding to gp130 attenuates signaling. Mutation of the SHP-2 binding site (Y2F) prolongs JAK/STAT activation and enhances APP gene induction and G-CSF sensitivity.
Key findings
- Both wild-type G-gp130 and G-gp130(Y2F) chimeric receptors activated JAK, induced STAT1/STAT3 DNA binding, and up-regulated α-fibrinogen and haptoglobin APP genes in H-35 cells.
- G-gp130(Y2F) failed to recruit SHP-2, and this correlated with prolonged tyrosine phosphorylation of receptor, JAK1, JAK2, and TYK2: wild-type signaling peaked at 5 min and declined rapidly by 30 min, whereas Y2F phosphorylation remained elevated for 30 min before declining.
- G-CSF was approximately twice as effective at inducing APP mRNA in G-gp130(Y2F) cells than in G-gp130 cells; haptoglobin mRNA was approximately twice as high in Y2F cells, while α-fibrinogen reached the same maximal mRNA level.
- G-gp130(Y2F) cells showed enhanced G-CSF sensitivity: fibrinogen production was detectable at 0.01 ng/ml G-CSF, whereas half-maximal stimulation required approximately 5 ng/ml in both lines; a G-gp130 clone expressing the same receptor amount as Y2F cells produced threefold lower fibrinogen induction.
- Overexpression of phosphatase-inactive SHP-2* enhanced signaling by wild-type G-gp130 but not by G-gp130(Y2F).
Methods
- Chimeric receptors consisting of the G-CSFR extracellular domain fused to wild-type or Y2F-mutated gp130 cytoplasmic domain were expressed in rat hepatoma H-35 cells by retroviral transduction; stable clonal lines were selected and screened for receptor expression and G-CSF-induced APP expression.
- Signaling was analyzed by EMSA for STAT1/STAT3 DNA binding, immunoprecipitation/Western blotting for receptor, JAK, STAT, and SHP-2 phosphorylation/association, Northern blotting for α-fibrinogen and haptoglobin mRNAs, and immunoelectrophoresis for secreted fibrinogen.
- A CAT reporter assay in HepG2 cells tested IL-6-responsive gene elements with wild-type or Y2F chimeric receptors and phosphatase-inactive SHP-2*; ¹²⁵I-G-CSF binding assays measured receptor surface binding.
Limitations
- The paper states that it is uncertain whether G-gp130(Y2F) signaling is truly independent of SHP-2, because indirect SHP-2 recruitment to tyrosine-phosphorylated proteins was observed at low levels.
- The paper notes no convincing experimental evidence that SHP-2 negatively regulates signaling through direct phosphatase action on JAKs, and it did not observe endogenous SHP-2 association with STAT3 or JAKs in the transduced hepatoma cells.
- The paper states that the modest effects of overexpressed SHP-2* may be explained by relatively high endogenous SHP-2 levels in HepG2 and H-35 cells, limiting competition.
- The paper notes that STAT3 half-life measurements were likely influenced by prolonged cycloheximide treatment and showed no statistically significant differences.
- Evident from the text: the G-gp130(Y2F) lines expressed consistently less receptor than G-gp130 lines, and several comparisons relied on selected clonal lines with differing receptor levels.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 8 cited sources checked · 0 supported · 0 flagged
- Findingown data
Maximal level of fibrinogen expression was somewhat higher in G-gp130(Y2F) cells than in G-gp130 cells.
“While the G-CSF responses in the two transduced cell lines were similar, in that approximately 5 ng of G-CSF per ml was required for half-maximal stimulation, the production of fibrinogen was already detectable in G-gp130(Y2F) cells at the lowest concentration tested (0.01 ng/ml), and the maximal level of expression was somewhat higher.”
Quote in the paperNot a substantial claim - Findingown data
In G-gp130 cells, maximal tyrosine phosphorylation of the receptors, JAK1, JAK2, and TYK2 was attained after a 5-min treatment with G-CSF, with rapid loss of signal by 30 min.
“In G-gp130 cells, maximal tyrosine phosphorylation of the receptors, JAK1, JAK2, and TYK2 was attained after a 5-min treatment with G-CSF, with rapid loss of signal by 30 min.”
Quote in the paperSubstantial claim - Findingown data
H-35 cells ectopically expressing G-gp130(Y2F) displayed an enhanced sensitivity to G-CSF.
“H-35 cells ectopically expressing G-gp130(Y2F) were also found to display an enhanced sensitivity to G-CSF”
Quote in the paperNot a substantial claim - Findingown data
Most of the receptor proteins were lost by 90 min.
“Most of the receptor proteins were lost by 90 min.”
Quote in the paperSubstantial claim - Findingown data
In G-gp130(Y2F)-expressing cells following G-CSF treatment, the associated JAK activity was maintained at elevated levels and for an extended period compared to G-gp130 cells.
“Moreover, the tyrosine phosphorylation state of the chimeric receptor, the associated JAK activity, and the induced DNA binding activity of STAT1 and STAT3 were maintained at elevated levels and for an extended period of time in G-gp130(Y2F)-expressing cells following G-CSF treatment compared to that in cells displaying the G-gp130 receptor.”
Quote in the paperSubstantial claim
- Findingown data
Fibrinogen production was detectable in G-gp130(Y2F) cells at the lowest G-CSF concentration tested (0.01 ng/ml).
“While the G-CSF responses in the two transduced cell lines were similar, in that approximately 5 ng of G-CSF per ml was required for half-maximal stimulation, the production of fibrinogen was already detectable in G-gp130(Y2F) cells at the lowest concentration tested (0.01 ng/ml), and the maximal level of expression was somewhat higher.”
Quote in the paperNot a substantial claim - Findingown data
In G-gp130(Y2F)-expressing cells following G-CSF treatment, the tyrosine phosphorylation state of the chimeric receptor was maintained at elevated levels and for an extended period compared to G-gp130 cells.
“Moreover, the tyrosine phosphorylation state of the chimeric receptor, the associated JAK activity, and the induced DNA binding activity of STAT1 and STAT3 were maintained at elevated levels and for an extended period of time in G-gp130(Y2F)-expressing cells following G-CSF treatment compared to that in cells displaying the G-gp130 receptor.”
Quote in the paperSubstantial claim - Findingown data
SHP-2 is recruited to gp130 upon activation by ligand binding.
“The results showed that SHP-2 is recruited to gp130 upon activation by ligand binding.”
Quote in the paperSubstantial claim - Findingown data
The difference in G-CSF dose response between the two G-gp130 cell lines was more clearly seen in amounts of APP secreted into the culture medium over 24 h.
“The difference in the G-CSF dose response between the two G-gp130 cell lines was more clearly seen in the amounts of APP secreted into the culture medium over the 24-h treatment period (Fig. 7 shows fibrinogen as an example).”
Quote in the paperNot a substantial claim - Findingown data
The cellular concentrations of both G-gp130 and G-gp130(Y2F) appeared to decline with roughly the same kinetics, regardless of whether the cells had been treated with G-CSF.
“In so far as this technique allowed an estimate of receptor amounts, the cellular concentrations of both G-gp130 and G-gp130(Y2F) appeared to decline with roughly the same kinetics, regardless of whether the cells had been treated with G-CSF.”
Quote in the paperSubstantial claim - Findingown data
The Y2F mutation led to prolonged phosphorylation of receptors, JAK, and STATs.
“Prevention of this binding by the Y2F mutation led to an enhanced signaling response that was associated with prolonged phosphorylation of the receptors, JAK, and STATs, extended DNA binding of the STAT proteins, and elevated transcription of APP genes.”
Quote in the paperSubstantial claim - Findingown data
In G-CSF-treated G-gp130(Y2F) cells, elevated levels of tyrosine-phosphorylated receptors and JAKs persisted for 30 min before declining to basal levels.
“In contrast, in G-CSF-treated G-gp130(Y2F) cells, elevated levels of tyrosine-phosphorylated receptors and JAKs persisted for 30 min before declining to basal levels.”
Quote in the paperSubstantial claim - Findingown data
The half-life of immunodetectable STAT3 was approximately 100 min in H-35 cells treated with or without cytokines.
“The kinetic analysis indicated a half-life of immunodetectable STAT3 of approximately 100 min in H-35 cells treated with or without cytokines.”
Quote in the paperSubstantial claim - Findingown data
G-CSF was approximately twice as effective in G-gp130(Y2F) cells than in G-gp130 cells at inducing APP mRNA.
“G-CSF was approximately twice as effective in G-gp130(Y2F) cells than in G-gp130 cells, in agreement with the noted difference in STAT3 activation in these cells.”
Quote in the paperSubstantial claim- Rests on an assumption: The observed differences between G-gp130 and G-gp130(Y2F) cells are due to loss of SHP-2 recruitment rather than differences in receptor expression levels.
- Findingown data
SHP-2* is ineffective on signaling by G-gp130(Y2F).
“Also, as expected, SHP-2* was ineffective on the signaling by the G-gp130(Y2F).”
Quote in the paperSubstantial claim - Findingown data
H-35 cells transduced with retroviral vectors for G-gp130 and G-gp130(Y2F) yielded significant expression of the chimeric receptors.
“H-35 cells transduced with retroviral vectors for G-gp130 and G-gp130 (Y2F) yielded significant expression of the chimeric receptors.”
Quote in the paperSubstantial claim - Findingown data
H-35 cells ectopically expressing G-gp130(Y2F) displayed a higher level of induction of APP genes.
“and a higher level of induction of APP genes.”
Quote in the paperSubstantial claim - Findingown data
Both chimeric receptors G-gp130 and G-gp130(Y2F) transmitted a G-CSF-induced signal characteristic of that triggered by IL-6 through the endogenous gp130 receptor.
“Both chimeric receptors transmitted a G-CSF-induced signal characteristic of that triggered by IL-6 through the endogenous gp130 receptor”
Quote in the paperSubstantial claim - Findingown data
The Y2F mutation led to elevated transcription of APP genes.
“Prevention of this binding by the Y2F mutation led to an enhanced signaling response that was associated with prolonged phosphorylation of the receptors, JAK, and STATs, extended DNA binding of the STAT proteins, and elevated transcription of APP genes.”
Quote in the paperSubstantial claim - Findingown data
G-gp130(Y2F) has a more prominent signaling action than G-gp130.
“The mRNA analysis, as well as the CAT regulation (Fig. 6), indicated a more prominent signaling action by G-gp130(Y2F) than by G-gp130.”
- Also stated in: § DISCUSSION · plain
“Prevention of this binding by the Y2F mutation led to an enhanced signaling response that was associated with prolonged phosphorylation of the receptors, JAK, and STATs, extended DNA binding of the STAT proteins, and elevated transcription of APP genes.”
Quote in the paperSubstantial claim - Also stated in: § DISCUSSION · plain
- Findingown data
Essentially the same time course of STAT3 reduction was detected in G-gp130 and G-gp130(Y2F) cells after either G-CSF or IL-6 treatment.
“Essentially the same time course of STAT3 reduction was detected in G-gp130 and G-gp130(Y2F) cells after either G-CSF or IL-6 treatment.”
Quote in the paperSubstantial claim - Findingown data
IL-6 responses of parental and transduced cell lines were essentially indistinguishable.
“The IL-6 responses of the parental and the transduced cell lines proved to be essentially indistinguishable (Fig. 7 shows only the parental H-35 cells).”
Quote in the paperNot a substantial claim - Findingown data
Overexpression of phosphatase-inactive SHP-2* enhances gene-regulatory effects by endogenous IL-6 receptor and G-gp130 in transfected HepG2 cells.
“overexpression of SHP-2* enhanced the gene-regulatory effects by endogenous IL-6 receptor and G-gp130.”
Quote in the paperSubstantial claim - Findingown data
The greater induction of APP mRNA in G-gp130(Y2F) cells was manifested in an enhanced sensitivity of the cells to G-CSF.
“The greater induction of APP mRNA in G-gp130(Y2F) cells was also manifested in an enhanced sensitivity of the cells to G-CSF (Fig. 6B).”
Quote in the paperNot a substantial claim - Findingown data
Mutation of the SHP-2 interaction site in G-gp130(Y2F) abrogated ligand-activated receptor recruitment of SHP-2.
“mutation of the SHP-2 interaction site in G-gp130(Y2F) abrogated ligand-activated receptor recruitment of SHP-2 as expected.”
Quote in the paperSubstantial claim - Findingown data
Approximately 5 ng of G-CSF per ml was required for half-maximal stimulation in both transduced cell lines.
“While the G-CSF responses in the two transduced cell lines were similar, in that approximately 5 ng of G-CSF per ml was required for half-maximal stimulation, the production of fibrinogen was already detectable in G-gp130(Y2F) cells at the lowest concentration tested (0.01 ng/ml), and the maximal level of expression was somewhat higher.”
Quote in the paperSubstantial claim - Findingown data
SHP-2 recruited into gp130 can act as a negative regulator of JAK in hepatoma cells.
“Surprisingly, our data show that SHP-2 recruited into gp130 can act as a negative regulator of JAK in hepatoma cells.”
Quote in the paperSubstantial claim- The authors state this as an assumption: SHP-2 acts soon after signal initiation and explains the effects on downstream targets of JAKs, e.g., STAT recruitment and activation by phosphorylation.
- Findingown data
10 ng of G-CSF per ml induced a strong APP mRNA signal in G-gp130(Y2F) cells but not in G-gp130 cells.
“For instance, 10 ng of G-CSF per ml induced a strong APP mRNA signal in G-gp130(Y2F) cells but not in G-gp130 cells.”
Quote in the paperNot a substantial claim - Findingown data
The Y2F mutation led to extended DNA binding of STAT proteins.
“Prevention of this binding by the Y2F mutation led to an enhanced signaling response that was associated with prolonged phosphorylation of the receptors, JAK, and STATs, extended DNA binding of the STAT proteins, and elevated transcription of APP genes.”
Quote in the paperSubstantial claim - Findingown data
Receptor-transduced cells displayed a significantly increased ligand binding activity, with cells expressing G-gp130 binding on average four times more G-CSF than those expressing G-gp130(Y2F).
“The receptor-transduced cells displayed a significantly increased ligand binding activity, with cells expressing G-gp130 binding on average four times more G-CSF than those expressing G-gp130(Y2F).”
Quote in the paperNot a substantial claim - Findingown data
In G-gp130(Y2F)-expressing cells following G-CSF treatment, the induced DNA binding activity of STAT1 and STAT3 was maintained at elevated levels and for an extended period compared to G-gp130 cells.
“Moreover, the tyrosine phosphorylation state of the chimeric receptor, the associated JAK activity, and the induced DNA binding activity of STAT1 and STAT3 were maintained at elevated levels and for an extended period of time in G-gp130(Y2F)-expressing cells following G-CSF treatment compared to that in cells displaying the G-gp130 receptor.”
Quote in the paperSubstantial claim - Findingown data
IL-6 induced α-fibrinogen and haptoglobin mRNAs in both cell lines to the same levels.
“Whereas IL-6 induced ␣-fibrinogen and haptoglobin mRNAs in both cell lines to the same levels”
Quote in the paperSubstantial claim - Findingown data
A low-level recovery of a G-CSF-induced association of SHP-2 with tyrosine-phosphorylated protein was noted in G-gp130(Y2F) cells.
“In fact, we noted a low-level recovery of a G-CSF-induced association of SHP-2 with tyrosine-phosphorylated protein in G-gp130(Y2F) cells (Fig. 3B) that may arise from such an indirect pathway.”
Quote in the paperNot a substantial claim - Interpretationown data
The APP gene-inducing action of wild-type gp130 is moderated by the recruitment of SHP-2.
“The data thus far suggested that the APP gene-inducing action of wild-type gp130 was moderated by the recruitment of SHP-2.”
Quote in the paperSubstantial claim - Premisecitation
Truncated gp130 forms that lack the SHP-2 binding site still deliver detectable MAPK activation.
“However, truncated gp130 forms that lack the SHP-2 binding site still deliver a detectable MAPK activation (36,41) that is interpreted to account for minimal growth stimulation (36).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [36]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [41]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
The elevated DNA binding activity of STATs and the phosphotyrosine STAT3 level are the result of prolonged kinase activity and not of a slower STAT3 turnover.
“Taking these data together, we interpret the elevated DNA binding activity of STATs (Fig. 5A) and the phosphotyrosine STAT3 level (Fig. 5B) to be the result of prolonged kinase activity and not of a slower STAT3 turnover.”
Quote in the paperSubstantial claim- Rests on an assumption: SHP-2 acts directly to dephosphorylate JAKs or receptor-associated kinases to attenuate gp130 signaling.
- Interpretationown data
The Y2F mutation enhanced the signaling activity of the receptor such that many fewer receptors were needed to attain the level of APP induction mediated by the wild-type receptor.
“The data strongly suggest that the Y2F mutation of gp130 had not appreciably altered the affinity of the chimeric receptor for G-CSF interaction (i.e., the same concentration of G-CSF induced the half-maximal response) but enhanced the signaling activity of the receptor such that many fewer receptors were needed to attain the level of APP induc- tion mediated by the wild-type receptor.”
Quote in the paperSubstantial claim - Interpretationown data
The induction of APP genes by gp130 signaling is not abrogated by the Y2 mutation.
“Here, we report that the induction of APP genes by gp130 signaling differs from gp130-mediated growth control in that it is not abrogated by the Y2 mutation”
Quote in the paperSubstantial claim - Interpretationreasoning
A critical contribution of the gp130-regulated MAPK pathway to the induction of APP genes appears unlikely.
“Hence, while SHP-2 may play a role in engaging the MAPK pathway as part of the gp130 signaling, a critical contribution of the gp130-regulated MAPK pathway to the induction of APP genes appears unlikely.”
Quote in the paperSubstantial claim - Interpretationown data
Substrate specificity of SHP-2 appears to be determined by its association with the receptor rather than by direct binding to JAK or STAT.
“Substrate specificity of SHP-2 appears to be determined by its association with the receptor rather than by direct binding to a JAK or STAT, since we did not observe in our receptor-transduced hepatoma cell line an association of the endogenous SHP-2 with STAT3 or JAKs (data not shown).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: SHP-2, once phosphorylated at the receptor site, dissociates from gp130 and may associate with various cellular and membrane proteins.
- Interpretationcitation
The loss of SHP-2 from immunoprecipitated G-gp130(Y2F) indicates that tyrosine residue Y2 is critical for binding of SHP-2 through its SH-2 domain.
“The loss of SHP-2 from immunoprecipitated G-gp130(Y2F) attested to the relevance of the tyrosine residue (Y2) as being critical for binding of SHP-2 through its SH-2 domain (14).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
The increase in cellular STAT3 level following extended treatment was previously shown to be the result of cytokine-induced STAT3 expression.
“This increase was previously shown to be the result of cytokine-induced STAT3 expression (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
gp130 signaling for APP gene induction in hepatic cells differs qualitatively from that controlling the proliferative response in hematopoietic cells in not being strictly dependent on SHP-2.
“These results indicate that gp130 signaling for APP gene induction in hepatic cells differs qualitatively from that controlling the proliferative response in hematopoietic cells in not being strictly dependent on SHP-2.”
Quote in the paperSubstantial claim- Rests on an assumption: The Y2F mutation in the chimeric gp130 receptor affects only SHP-2 binding and not other signaling functions.
- Rests on an assumption: The observed differences between G-gp130 and G-gp130(Y2F) cells are due to loss of SHP-2 recruitment rather than differences in receptor expression levels.
- Interpretationown data
In wild-type gp130, recruited SHP-2 attenuates signaling intensity.
“From this information, we conclude that in the wild-type gp130 the recruited SHP-2 attenuates the signaling intensity but that SHP-2 is not essential for APP gene expression.”
Quote in the paperSubstantial claim - Interpretationreasoning
SHP-2 is not crucial for eventual down-regulation of the gp130 signal.
“SHP-2 is not crucial for APP gene induction or for eventual down-regulation of the gp130 signal.”
Quote in the paperSubstantial claim - Interpretationreasoning
SHP-2 is not essential for APP gene expression.
“From this information, we conclude that in the wild-type gp130 the recruited SHP-2 attenuates the signaling intensity but that SHP-2 is not essential for APP gene expression.”
Quote in the paperSubstantial claim - Interpretationown data
SHP-2 functions normally to attenuate gp130-mediated signaling in hepatic (and perhaps other) cells by moderating JAK action.
“The data further suggest that SHP-2 functions normally to attenuate gp130-mediated signaling in hepatic (and, perhaps, other) cells by moderating JAK action.”
Quote in the paperSubstantial claim- Rests on an assumption: The Y2F mutation in the chimeric gp130 receptor affects only SHP-2 binding and not other signaling functions.
- Rests on an assumption: SHP-2 acts directly to dephosphorylate JAKs or receptor-associated kinases to attenuate gp130 signaling.
- Interpretationown data
Relatively fast turnover of the chimeric receptors, rather than the specific action of a tyrosine phosphatase, may account for the loss of tyrosine-phosphorylated proteins noted after 1 h of cytokine treatment.
“Thus, relatively fast turnover of the chimeric receptors, rather than the specific action of a tyrosine phosphatase, may account for the loss of tyrosine-phosphorylated proteins noted after 1 h of cytokine treatment (Fig. 4A).”
Quote in the paperSubstantial claim- Rests on an assumption: The Y2F mutation in the chimeric gp130 receptor affects only SHP-2 binding and not other signaling functions.
- Interpretationown data
The Y2F mutation of gp130 did not appreciably alter the affinity of the chimeric receptor for G-CSF interaction.
“The data strongly suggest that the Y2F mutation of gp130 had not appreciably altered the affinity of the chimeric receptor for G-CSF interaction (i.e., the same concentration of G-CSF induced the half-maximal response) but enhanced the signaling activity of the receptor such that many fewer receptors were needed to attain the level of APP induc- tion mediated by the wild-type receptor.”
Quote in the paperSubstantial claim - Interpretationreasoning
This study has defined a component of the gp130 signal pathway that distinguishes the regulation of differentiated genes from that of those that control cell proliferation.
“In conclusion, this study has defined a component of the gp130 signal pathway that distinguishes the regulation of”
Quote in the paperSubstantial claim - Interpretationreasoning
Even slightly enhanced gp130 signaling maintained for 24 h leads to significantly elevated accumulation of stable APP mRNA and corresponding accumulation of plasma protein in the medium.
“Even slightly enhanced gp130 signaling that is maintained for 24 h leads to a significantly elevated accumulation of stable APP mRNA and, consequently, to a corresponding accumulation of plasma protein in the medium.”
Quote in the paperSubstantial claim
- May combine two claims. 14
- Classified as probably not a substantial claim. 4
May combine two claims.
Findingown dataBoth G-gp130 and G-gp130(Y2F) up-regulated expression of the target APP genes, those for α-fibrinogen and haptoglobin.
“up-regulated expression of the target APP genes, those for ␣-fibrinogen and haptoglobin”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn a separate clonal line of G-gp130 cells (clone 2) expressing the same amount of G-gp130 proteins as G-gp130(Y2F) cells, the magnitude of induction of fibrinogen was threefold lower, while showing essentially the same G-CSF dose response as clone 1 or G-gp130(Y2F) cells.
“While showing essentially the same G-CSF dose response as clone 1 or the G-gp130(Y2F) cells, the magnitude of induction of fibrinogen was threefold lower in this cell line.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataG-CSF induced association of SHP-2 with G-gp130 but not G-gp130(Y2F).
“As expected, G-CSF induced association of SHP-2 with G-gp130 but not G-gp130(Y2F).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationThe cellular level of STAT3 increased again following extended hours of treatment and even exceeded the level detected in cells at 0 h.
“The analysis also revealed that the cellular level of STAT3 increased again following extended hours of treatment and even exceeded the level detected in cells at 0 h.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataBoth G-gp130 and G-gp130(Y2F) induced DNA binding activity by STAT1 and STAT3.
“induced DNA binding activity by STAT1 and STAT3”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataOverexpression of the enzymatically inactive SHP-2 enhanced the signaling by the wild-type but not by the Y2F mutant G-gp130 receptor.
“Overexpression of the enzymatically inactive SHP-2 enhanced the signaling by the wild-type but not by the Y2F mutant G-gp130 receptor.”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationIn transduced G-gp130(Y2F) cells, detectable ERK1 and ERK2 tyrosine phosphorylation occurred following G-CSF treatment, but the magnitude was much lower than in G-gp130 cells.
“Similarly, analysis of transduced G-gp130(Y2F) cells showed detectable ERK1 and ERK2 tyrosine phosphorylation following G-CSF treatment, although the magnitude of activation was much lower than that observed for G-gp130 cells (22a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (22a)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataCell lines with G-gp130(Y2F) showed consistently less receptor expression than those with G-gp130.
“Interestingly, the cell lines with G-gp130(Y2F) showed consistently less receptor expression than those with G-gp130.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe DNA binding activity of STAT1 and STAT3 and the relative amounts of tyrosine-phosphorylated STAT3 persisted longer in G-gp130(Y2F) cells than in G-gp130 cells.
“Time course analysis of G-CSF treatment indeed indicated that the DNA binding activity of STAT1 and STAT3 (Fig. 5A) and the relative amounts of tyrosine-phosphorylated STAT3 (Fig. 5B) persisted longer in G-gp130(Y2F) cells than in G-gp130 cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth G-gp130 and G-gp130(Y2F) activated the appropriate JAK.
“both activated the appropriate JAK”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe APP genes were not identically regulated, in that α-fibrinogen attained the same maximal mRNA level in both cell types after G-CSF treatment, whereas the haptoglobin mRNA level in G-gp130(Y2F) cells was approximately twice that in G-CSF-treated G-gp130 cells.
“The comparison also indicated that the APP genes were not identically regulated, in that ␣-fibrinogen attained the same maximal mRNA level in both cell types after G-CSF treatment, whereas the haptoglobin mRNA level in G-gp130(Y2F) cells was approximately twice that in G-CSF-treated G-gp130 cells.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataPrevention of SHP-2 recruitment enhances the signaling reaction and responsiveness of the cells to the cytokine, in part by prolonging the activity of JAKs.
“instead, prevention of SHP-2 recruitment enhances the signaling reaction and responsiveness of the cells to the cytokine, in part by prolonging the activity of JAKs.”
Quote in the paperSubstantial claim- Rests on an assumption: The Y2F mutation in the chimeric gp130 receptor affects only SHP-2 binding and not other signaling functions.
- Rests on an assumption: The observed differences between G-gp130 and G-gp130(Y2F) cells are due to loss of SHP-2 recruitment rather than differences in receptor expression levels.
May combine two claims.
Interpretationown dataThe modest effects of overexpressed SHP-2* may be explained in part by relatively high levels of endogenous SHP-2 proteins, which were similar in HepG2 and H-35 cells.
“The rather modest effects of the overexpressed SHP-2* may in part be explained by the relatively high levels of endogenous SHP-2 proteins, which, based on comparative Western blot data, were similar in HepG2 and H-35 cells (data not shown).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAbrogation of SHP-2 recruitment by gp130 negatively affects proliferation of hematopoietic cells, in part correlated with lower MAPK activity.
“Abrogation of SHP-2 recruitment by gp130 has been seen to negatively affect proliferation of hematopoietic cells, which was in part correlated with lower MAPK activity (8,14).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Study design and conductown dataThe measured STAT3 half-life was likely influenced by the prolonged treatment of cells with cycloheximide and showed no statistically significant differences.
“Although the measured STAT3 half-life was likely influenced by the prolonged treatment of cells with cycloheximide and showed no statistically significant differences”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningSHP-2 is likely a target for phosphorylation by gp130-associated kinases.
“Moreover, it is likely that SHP-2 is also a target for phosphorylation by gp130-associated kinases.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: SHP-2, once phosphorylated at the receptor site, dissociates from gp130 and may associate with various cellular and membrane proteins.
Classified as probably not a substantial claim.
PremisecitationThe phosphatase activity of SHP-2 is necessary for its moderating effect on gene induction in neuroblastoma cells.
“Recently, Symes et al. (46) demonstrated that the phosphatase activity of SHP-2 was necessary to achieve this moderating effect on gene induction in neuroblastoma cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Symes et al. [46]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
The paper relies on this without support.
The Y2F mutation in the chimeric gp130 receptor affects only SHP-2 binding and not other signaling functions.
“instead, prevention of SHP-2 recruitment enhances the signaling reaction and responsiveness of the cells to the cytokine, in part by prolonging the activity of JAKs.”
The paper relies on this without support.
The observed differences between G-gp130 and G-gp130(Y2F) cells are due to loss of SHP-2 recruitment rather than differences in receptor expression levels.
“Interestingly, the cell lines with G-gp130(Y2F) showed consistently less receptor expression than those with G-gp130.”
“The lines had been initially selected because of their comparable levels of maximally G-CSF-induced APP expression.”
The paper relies on this without support.
SHP-2 acts directly to dephosphorylate JAKs or receptor-associated kinases to attenuate gp130 signaling.
“The data further suggest that SHP-2 functions normally to attenuate gp130-mediated signaling in hepatic (and, perhaps, other) cells by moderating JAK action.”
The authors state this as an assumption.
SHP-2, once phosphorylated at the receptor site, dissociates from gp130 and may associate with various cellular and membrane proteins.
“we assume that SHP-2, once phosphorylated at the receptor site, disassociates from gp130 and may associate with various cellular and membrane proteins (9,19,21,28,29).”
The authors state this as an assumption.
SHP-2 acts soon after signal initiation and explains the effects on downstream targets of JAKs, e.g., STAT recruitment and activation by phosphorylation.
“we intuitively assume that SHP-2 acts soon after signal initiation and explains the effects on the downstream targets of JAKs, e.g., STAT recruitment and activation by phosphorylation.”
The paper relies on this without support.
The chimeric G-gp130 constructs can be tested in hepatoma cells independently of the endogenous gp130.
“The experimental approach was to examine the effect of mutating the suggested SHP-2 binding site in the chimeric G-gp130 constructs that could be tested in hepatoma cells independently of the endogenous gp130.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Northern blot RNA amount differs between methods and Figure 6
MinorThe Northern hybridization methods specify 25 or 5 g of total cellular RNA, but the Figure 6A caption specifies 20 g per lane.
“Total cellular RNA (25 or 5 g) was separated on a 1.5% agarose-formaldehyde gel and blotted onto a positively charged nylon filter (Schleicher and Schuell).”
“Total cellular RNA (20 g per lane) was analyzed by sequential Northern blot hybridization for the mRNAs for ␣-fibrinogen (␣-FB) and haptoglobin (HP).”
Cites
A family of cytokine-inducible inhibitors of signalling
Starr, R., Willson, T. A., Viney, E. M., Murray, L. J. L., Rayner, J. R., Jenkins, B. J., Gonda, T. J., Alexander, W. S., Metcalf, D., Nicola, N. A., et al. (1997) · Nature · doi:10.1038/43206 · Cited by 2,066 · see citing works
Gauldie, J., Richards, C. D., Harnish, D. C., Lansdorp, P. M., & Baumann, H. J. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.20.7251 · Cited by 1,635 · see citing works
Self-citationA new protein containing an SH2 domain that inhibits JAK kinases
Endo, T. A., Masuhara, M., Yokouchi, M., Suzuki, R., Sakamoto, H., Mitsui, K., Matsumoto, A., Tanimura, S., Ohtsubo, M., Misawa, H., et al. (1997) · Nature · doi:10.1038/43213 · Cited by 1,408 · see citing works
Miller, A. D., & Buttimore, C. (1986) · Molecular and Cellular Biology · doi:10.1128/mcb.6.8.2895-2902.1986 · Cited by 1,371 · see citing works
Structure and function of a new STAT-induced STAT inhibitor
Naka, T., Narazaki, M., Hirata, M., Matsumoto, T., Minamoto, S., Aono, A., Nishimoto, N., Kajita, T., Taga, T., Yoshizaki, K., et al. (1997) · Nature · doi:10.1038/43219 · Cited by 1,287 · see citing works
Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II
Sturgill, T. W., Ray, L. B., ERIKSON, E., & Maller, J. L. (1988) · Nature · doi:10.1038/334715a0 · Cited by 1,017 · see citing works
Stahl, N., Farruggella, T. J., Boulton, T. G., Zhong, Z., Darnell, J. E., & Yancopoulos, G. D. (1995) · Science · doi:10.1126/science.7871433 · Cited by 979 · see citing works
Association and Activation of Jak-Tyk Kinases by CNTF-LIF-OSM-IL-6 β Receptor Components
Stahl, N., Boulton, T. G., Farruggella, T., Ip, N. Y., Davis, S., Witthuhn, B. A., Quelle, F. W., Silvennoinen, O., Barbieri, G., Pellegrini, S., et al. (1994) · Science · doi:10.1126/science.8272873 · Cited by 979 · see citing works
Klingmüller, U., Lorenz, U. M., Cantley, L. C., Neel, B. G., & Lodish, H. F. (1995) · Cell · doi:10.1016/0092-8674(95)90351-8 · Cited by 927 · see citing works
Lütticken, C., Wegenka, U. M., Yuan, J., Buschmann, J., Schindler, C., Ziemiecki, A., Harpur, A. G., Wilks, A. F., Yasukawa, K., Taga, T., et al. (1994) · Science · doi:10.1126/science.8272872 · Cited by 814 · cited 3× · see citing works
“A similar phosphorylation-induced change in electrophoretic mobility was reported for the native gp130, which showed an increase in the apparent molecular mass from ; 155 to ;170 kDa (30).”
BackgroundA common nuclear signal transduction pathway activated by growth factor and cytokine receptors.
Sadowski, H., Shuai, K., Darnell, J., & Gilman, M. (1993) · Science · doi:10.1126/science.8397445 · Cited by 682 · see citing works
A family of proteins that inhibit signalling through tyrosine kinase receptors
Kharitonenkov, A., Chen, Z., Sures, I., Wang, H., Schilling, J., & Ullrich, A. (1997) · Nature · doi:10.1038/386181a0 · Cited by 662 · see citing works
Fukada, T., Hibi, M., Yamanaka, Y., Takahashi-Tezuka, M., Fujitani, Y., Yamaguchi, T., Nakajima, K., & Hirano, T. (1996) · Immunity · doi:10.1016/s1074-7613(00)80501-4 · Cited by 652 · see citing works
Mosley, B., Beckmann, M. P., March, C. J., Idzerda, R. L., Gimpel, S. D., VandenBos, T., Friend, D. J., Alpert, A., Anderson, D. M., Jackson, J. L., et al. (1989) · Cell · doi:10.1016/0092-8674(89)90295-x · Cited by 624 · see citing works
Murakami, M., Narazaki, M., Hibi, M., Yawata, H., Yasukawa, K., Hamaguchi, M., Taga, T., & Kishimoto, T. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.24.11349 · Cited by 589 · see citing works
A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase
Li, W., Nishimura, R., Kashishian, A., Batzer, A., Kim, W. J. H., Cooper, J. A., & Schlessinger, J. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.1.509-517.1994 · Cited by 482 · see citing works
The insulin receptor substrate 1 associates with the SH2-containing phosphotyrosine phosphatase Syp
Kuhné, M. R., Pawson, T. J., Lienhard, G. E., & Feng, G. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)50220-4 · Cited by 380 · see citing works
Baumann, H., Richards, C. D., & Gauldie, J. (1987) · The Journal of Immunology · doi:10.4049/jimmunol.139.12.4122 · Cited by 360 · see citing works
Self-citationMultiple Requirements for SHPTP2 in Epidermal Growth Factor-Mediated Cell Cycle Progression
Bennett, A. M., Hausdorff, S. F., O’Reilly, A. M., Freeman, R. M., & Neel, B. G. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.3.1189 · Cited by 246 · see citing works
Syp (SH-PTP2) is a positive mediator of growth factor-stimulated mitogenic signal transduction.
Xiao, S., Rose, D. W., Sasaoka, T., Maegawa, H., Burke, T. R., Roller, P. P., Shoelson, S. E., & Olefsky, J. M. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31955-5 · Cited by 241 · see citing works
Stimulation of Hepatic Acute Phase Response by Cytokines and Glucocorticoidsa
BAUMANN, H., Prowse, K. R., MARINKOVIĆ, S., Won, K. A., & Jahreis, G. P. (1989) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1989.tb24021.x · Cited by 240 · see citing works
Self-citationJackson, D. E., Ward, C. M., Wang, R., & Newman, P. J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.11.6986 · Cited by 212 · see citing works
Kazlauskas, A., Feng, G., Pawson, T. J., & Valius, M. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.15.6939 · Cited by 207 · see citing works
Leptin Receptor Action in Hepatic Cells
Wang, Y., Kuropatwinski, K. K., White, D. W., Hawley, T. S., Hawley, R. G., Tartaglia, L. A., & Baumann, H. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.26.16216 · Cited by 196 · see citing works
Self-citationMatsuda, T., Takahashi-Tezuka, M., Fukada, T., Okuyama, Y., Fujitani, Y., Tsukada, S., Mano, H., Hirai, H., Witte, O., & Hirano, T. (1995) · Blood · doi:10.1182/blood.v85.3.627.bloodjournal853627 · Cited by 158 · see citing works
Matsuda, T., Fukada, T., Takahashi-Tezuka, M., Okuyama, Y., Fujitani, Y., Hanazono, Y., Hirai, H., & Hirano, T. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.19.11037 · Cited by 142 · see citing works
Yin, T., Shen, R., Feng, G., & Yang, Y. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.2.1032 · Cited by 138 · see citing works
Case, R. D., Piccione, E., Wolf, G., Benett, A. M., Lechleider, R. J., Neel, B. G., & Shoelson, S. E. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)34083-8 · Cited by 133 · see citing works
Symes, A., Stahl, N., Reeves, S. A., Farruggella, T., Servidei, T., Gearan, T., Yancopouloš, G., & Fink, J. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00298-3 · Cited by 133 · see citing works
Baumann, H., Hill, R. E., Sauder, D. N., & Jahreis, G. P. (1986) · The Journal of Cell Biology · doi:10.1083/jcb.102.2.370 · Cited by 129 · see citing works
Self-citationProwse, K. R., & Baumann, H. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.1.42 · Cited by 116 · see citing works
Self-citationBaumann, H., Symes, A. J., Comeau, M. R., Morella, K. K., Wang, Y., Friend, D. J., Ziegler, S. F., Fink, J. S., & Gearing, D. P. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.1.138-146.1994 · Cited by 113 · see citing works
Self-citationSchiemann, W. P., Bartoe, J. L., & Nathanson, N. M. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.26.16631 · Cited by 95 · see citing works
Tauchi, T., Damen, J. E., Toyama, K., Feng, G., Broxmeyer, H., & Krystal, G. (1996) · Blood · doi:10.1182/blood.v87.11.4495.bloodjournal87114495 · Cited by 95 · see citing works
O’Mahoney, J. V., & Adams, T. E. (1994) · DNA and Cell Biology · doi:10.1089/dna.1994.13.1227 · Cited by 93 · see citing works
Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK
Takahashi-Tezuka, M., Hibi, M., Fujitani, Y., et al. (1997) · Oncogene · doi:10.1038/sj.onc.1201071 · Cited by 92 · see citing works
Kumar, G., Gupta, S., Wang, S., & Nel, A. E. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.153.10.4436 · Cited by 80 · see citing works
Lai, C., Ripperger, J. A., Morella, K. K., Wang, Y., Gearing, D. P., Horseman, N. D., Campos, S. P., Fey, G. H., & Baumann, H. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.40.23254 · Cited by 78 · see citing works
Self-citationInterleukin-3 Induces the Association of the Inositol 5-Phosphatase SHIP with SHP2
Liu, L., Damen, J. E., Ware, M. D., & Krystal, G. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.17.10998 · Cited by 73 · see citing works
Bone, H., Dechert, U., Jirik, F. R., Schrader, J. W., & Welham, M. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.22.14470 · Cited by 72 · see citing works
Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase
Giordano, V., Falco, G. D., Chiari, R., et al. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.158.9.4097 · Cited by 68 · see citing works
The Carboxyl-terminal Region of STAT3 Controls Gene Induction by the Mouse Haptoglobin Promoter
Kim, H., & Baumann, H. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.23.14571 · Cited by 68 · see citing works
Self-citationLai, C., Ripperger, J., Morella, K. K., Wang, Y., Gearing, D., Fey, G., & Baumann, H. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.25.14847 · Cited by 63 · see citing works
Self-citationCarlberg, K., & Rohrschneider, L. R. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.25.15943 · Cited by 56 · see citing works
Interleukin-11 Induces Complex Formation of Grb2, Fyn, and JAK2 in 3T3L1 Cells
Wang, X.-Y., Fuhrer, D. K., Marshall, M. S., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.47.27999 · Cited by 47 · see citing works
Immenschuh, S., Nagae, Y., Satoh, H., Baumann, H., & Müller‐Eberhard, U. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)99926-6 · Cited by 43 · see citing works
Self-citationInterleukin-2 induces tyrosine phosphorylation of SHP-2 through IL-2 receptor β chain
Adachi, M., Ishino, M., Torigoe, T., et al. (1997) · Oncogene · doi:10.1038/sj.onc.1200981 · Cited by 42 · see citing works
Insulin Modulates STAT3 Protein Activation and Gene Transcription in Hepatic Cells*
Campos, S. P., Wang, Y., & Baumann, H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.40.24418 · Cited by 39 · see citing works
Self-citationHawley, R. G., Lieu, F. H., Fong, A. Z. C., et al. (1996) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1996.tb52687.x · Cited by 39 · see citing works
Self-citationBehrmann, I., Janzen, C. J., Gerhartz, C., de Leur, H. S., Hermanns, H., Heesel, B., Graeve, L., Horn, F., Tavernier, J., & Heinrich, P. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.8.5269 · Cited by 39 · see citing works
Interferon-β Interrupts Interleukin-6–Dependent Signaling Events in Myeloma Cells
Berger, L., & Hawley, R. G. (1997) · Blood · doi:10.1182/blood.v89.1.261 · Cited by 38 · see citing works
Self-citationInterferon-beta interrupts interleukin-6-dependent signaling events in myeloma cells.
Berger, L. C., & Hawley, R. G. (1997) · Blood · doi:10.1182/blood.v89.1.261.261_261_271 · Cited by 37
Self-citationMorella, K. K., Lai, C., Kumaki, S., Kumaki, N., Wang, Y., Bluman, E. M., Witthuhn, B., Ihle, J., Giri, J., Gearing, D., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.14.8298 · Cited by 31 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 4
- Baumann H., 1994, Mol. Cell. Biol., 14, 138
- Li W., 1994, Mol. Cell. Biol., 14, 509
- Miller A. D., 1986, Mol. Cell. Biol., 6, 2895
- Prowse K. R., 1988, Mol. Cell. Biol., 8, 42
Cited by
Sorted by citations
Principles of interleukin (IL)-6-type cytokine signalling and its regulation
HEINRICH, P. C., BEHRMANN, I., HAAN, S., HERMANNS, H. M., MÜLLER-NEWEN, G., & SCHAPER, F. (2003) · Biochemical Journal · doi:10.1042/bj20030407 · Cited by 3,272 · see citing works
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
Hirano, T., Ishihara, K., & Hibi, M. (2000) · Oncogene · doi:10.1038/sj.onc.1203551 · Cited by 1,187 · see citing works
“In contrast, mutating tyrosine 759 or overexpressing a SHP2 mutant with an inactive catalytic domain enhances the STAT3-mediated biological actions in hepatocytes and neuroblastoma cells (Kim et al., 1998; Symes et al., 1997), suggesting a role for SHP2 in attenuating gp130-mediated signals.”
BackgroundIL-6 signal transduction and its physiological roles: the signal orchestration model
Kamimura, D., Ishihara, K., & Hirano, T. (2003) · Reviews of Physiology, Biochemistry and Pharmacology · doi:10.1007/s10254-003-0012-2 · Cited by 673 · see citing works
“A catalytically inactive mutant of SHP-2 enhances the activation of the APP gene promoter in response to gp130 stimulation, but this enhancement is not observed when Y759 in gp130 is mutated (Kim et al. 1998; Schaper et al. 1998; Kim and Baumann 1999).”
BackgroundSignal Transducer and Activator of Transcription‐3, Inflammation, and Cancer
Aggarwal, B. B., Kunnumakkara, A. B., Harikumar, K. B., Gupta, S. R., Tharakan, S. T., Koca, C., Dey, S., & Sung, B. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.04911.x · Cited by 652 · see citing works
Negative Regulation of Cytokine Signaling Pathways
Yasukawa, H., Sasaki, A. T., & Yoshimura, A. (2000) · Annual Review of Immunology · doi:10.1146/annurev.immunol.18.1.143 · Cited by 596 · see citing works
Suppression of SHP-2 and ERK Signalling Promotes Self-Renewal of Mouse Embryonic Stem Cells
Burdon, T., Stracey, C., Chambers, I., Nichols, J., & Smith, A. G. (1999) · Developmental Biology · doi:10.1006/dbio.1999.9265 · Cited by 585 · see citing works
Boyd, J. G., & Gordon, T. (2003) · Molecular Neurobiology · doi:10.1385/mn:27:3:277 · Cited by 515 · see citing works
Schmitz, J., Weissenbach, M., Haan, S., Heinrich, P. C., & Schaper, F. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.17.12848 · Cited by 388 · see citing works
STAT3 Is Required for the gp130-mediated Full Activation of the c-myc Gene
Kiuchi, N., Nakajima, K., Ichiba, M., Fukada, T., Narimatsu, M., Mizuno, K., Hibi, M., & Hirano, T. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.189.1.63 · Cited by 396 · see citing works
“This may be explained by an inhibitory effect of SHP-2, which is activated through the tyrosine phosphorylation module at Y759, on the STAT3 activity (74).”
Leukemia-Inhibitory Factor--Neuroimmune Modulator of Endocrine Function
Auernhammer, C. J., & Melmed, S. K. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.3.0400 · Cited by 263 · see citing works
Ohtani, T., Ishihara, K., Atsumi, T., Nishida, K., Kaneko, Y., Miyata, T., Itoh, S., Narimatsu, M., Maeda, H., Fukada, T., et al. (2000) · Immunity · doi:10.1016/s1074-7613(00)80162-4 · Cited by 284 · see citing works
“, 1996), although its negative role is also suggested in STAT3-mediated Japan Science and Technology Corporation (JST) 2–2 Yamada-oka, Suita biological actions (Symes et al., 1997; Kim et al., 1998).”
BackgroundInfluentialStat3: linking inflammation to epithelial cancer - more than a "gut" feeling?
Jarnicki, A., Putoczki, T. L., & Ernst, M. (2010) · Cell Division · doi:10.1186/1747-1028-5-14 · Cited by 240 · see citing works
“Irie-Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, et al.: CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling.”
BackgroundInfluentialSHP2 and SOCS3 Contribute to Tyr-759-dependent Attenuation of Interleukin-6 Signaling through gp130
Lehmann, U., Schmitz, J., Weissenbach, M., Sobota, R. M., Hörtner, M., Friederichs, K., Behrmann, I., Tsiaris, W., Sasaki, A., Schneider-Mergener, J., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210552200 · Cited by 236 · see citing works
Sengupta, T. K., Talbot, E. S., Scherle, P., & Ivashkiv, L. (1998) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.95.19.11107 · Cited by 245 · see citing works
Sarapultsev, A., Gusev, E., Komelkova, M. V., Utepova, I. A., Luo, S., & Hu, D. (2023) · Molecular Biomedicine · doi:10.1186/s43556-023-00151-1 · Cited by 226 · see citing works
Signaling Mechanisms Regulating Self-Renewal and Differentiation of Pluripotent Embryonic Stem Cells
Burdon, T., Chambers, I., Stracey, C., Niwa, H., & Smith, A. G. (1999) · Cells Tissues Organs · doi:10.1159/000016693 · Cited by 191 · see citing works
“…of the SHP-2 binding site in gp130 or overexpression of catalytically inactive SHP-2 mutants results in enhanced activation of JAK kinases, prolonged phosphorylation of gp130 and STAT3, and increased transcription of STAT3 target genes [Symes et al., 1997; Kim et al., 1998; Servidei et al., 1998].”
BackgroundInterleukin-6 signalling: More than Jaks and STATs
Eulenfeld, R., Dittrich, A., Khouri, C., Müller, P. J., Mütze, B., Wolf, A., & Schaper, F. (2012) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2011.09.010 · Cited by 171 · see citing works
Kim, H., & Baumann, H. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.8.5326 · Cited by 170 · see citing works
“Mutational studies of gp130, the signal-transducing receptor subunit for IL-6 cytokines, demonstrates that tyrosine residues Y769, Y814, Y905, and Y915, which are part of the YXXQ motif, upon phosphorylation, are docking sites for STAT3 or STAT1 (23, 63), whereas Y759 is the site of SHP-2 interaction (19, 34).”
BackgroundResultInfluentialSelf-citationMyers, M. G., Mendez, R., Shi, P., Pierce, J. H., Rhoads, R., & White, M. F. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.41.26908 · Cited by 164 · see citing works
Functional Interaction of STAT3 Transcription Factor with the Cell Cycle Inhibitor p21
Coqueret, O., & Gascan, H. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001601200 · Cited by 152 · see citing works
Suppressors of Cytokine Signaling (SOCS): Inhibitors of the JAK/STAT Pathway
Cooney, R. N. (2002) · Shock · doi:10.1097/00024382-200202000-00001 · Cited by 152 · see citing works
The role of the interleukin‐6 family of cytokines in inflammatory arthritis and bone turnover
Wong, P. K. K., Campbell, I. K., Egan, P. J., Ernst, M., & Wicks, I. P. (2003) · Arthritis & Rheumatism · doi:10.1002/art.10943 · Cited by 140 · see citing works
Kortylewski, M., Heinrich, P., Mackiewicz, A., Schniertshauer, U., Klingmüller, U., Nakajima, K., Hirano, T., Horn, F., & Behrmann, I. (1999) · Oncogene · doi:10.1038/sj.onc.1202708 · Cited by 146 · see citing works
“Activation of the SHP-2 phosphatase may further lead to downregulation of the signal (Kim et al., 1998; Schaper et al., 1998; Symes et al., 1997).”
BackgroundStofega, M. R., Herrington, J. B., Billestrup, N., & Carter‐Su, C. (2000) · Molecular Endocrinology · doi:10.1210/mend.14.9.0513 · Cited by 134 · see citing works
“Consistent with prolonged tyrosyl phosphorylation of GHR resulting from mutation of the SHP-2 binding site in GHR, mutation of the SHP-2 binding site in the gp130 subunit of the leukemiainhibitory factor (LIF) receptor prolongs tyrosyl phosphorylation of gp130 in response to ligand (34).”
BackgroundDominant-negative mutations in human IL6ST underlie hyper-IgE syndrome
Béziat, V., Tavernier, S. J., Chen, Y., Ma, C. S., Materna, M., Laurence, A. D. J., Staal, J., Aschenbrenner, D., Roels, L., Worley, L., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20191804 · Cited by 134 · see citing works
“The T761fs mutant from P2 to P4 was the only variant retaining the tyrosine in position 759 of GP130 (Y759) previously shown to recruit SHP2 and activate the MAPK pathway (Stahl et al., 1995; Symes et al., 1997; Schaper et al., 1998; Kim et al., 1998).”
Kalliolias, G. D., & Ivashkiv, L. B. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.9.6325 · Cited by 132 · see citing works
The Janus kinase family of protein tyrosine kinases and their role in signaling
Yeh, T. C., & Pellegrini, S. (1999) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050392 · Cited by 126 · see citing works
Role of the SHP-2 tyrosine phosphatase in cytokine-induced signaling and cellular response
Qu, C. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(02)00322-1 · Cited by 120 · see citing works
Augmented gp130‐mediated cytokine signalling accompanies human gastric cancer progression
Cb, J., Judd, L. M., Menheniott, T. R., Kronborg, I., Dow, C., Yeomans, N. D., Boussioutas, A., Robb, L. G., & Giraud, A. (2007) · The Journal of Pathology · doi:10.1002/path.2218 · Cited by 117 · see citing works
“CagA has been shown in vitro to interact with the ras/MAPK signalling intermediate SHP-2 [4,6] and these findings have been corroborated in humans in vivo [20].”
Concerted Functions of Gab1 and Shp2 in Liver Regeneration and Hepatoprotection
Bard-Chapeau, E. A., Yuan, J., Droin, N. M., Long, S., Zhang, E. E., Nguyen, T. V., & Feng, G. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.02253-05 · Cited by 115 · see citing works
“7A), consistent with a previous observation that Shp2 is not required for the induction of acute-phase plasma protein genes in hepatic cells (21).”
BackgroundCross-Talk Between IL-1 and IL-6 Signaling Pathways in Rheumatoid Arthritis Synovial Fibroblasts
Deon, D., Ahmed, S. T., Tai, K. W., Scaletta, N., Herrero, C., Lee, I.-H., Krause, A., & Ivashkiv, L. B. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.9.5395 · Cited by 113 · see citing works
“Inhibition of protein synthesis by cycloheximide resulted in a rapid loss of IL-6 signaling (within 1 h), possibly explained by loss of IL-6R expression, as previously reported by others (56).”
ResultMeier, J. A., Hyun, M., Cantwell, M. T., Raza, A., Mertens, C., Raje, V., Sisler, J. D., Tracy, E., Torres-Odio, S., Gispert, S., et al. (2017) · Science Signaling · doi:10.1126/scisignal.aag2588 · Cited by 112 · see citing works
“To further explore this possibility we took advantage of cell lines containing chimeric receptors expressing the extracellular domain of granulocyte colony stimulating factor (GCSF) coupled intracellularly to gp130(19).”
Self-citationChattopadhyay, S., Tracy, E., Liang, P., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m609655200 · Cited by 108 · see citing works
Self-citationBode, J., Gatsios, P., Ludwig, S., Rapp, U., Häussinger, D., Heinrich, P., & Graeve, L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.30222 · Cited by 114 · see citing works
Dynamic regulation of Bcl6 in follicular helper CD4 T (Tfh) cells
Choi, Y. S., Kotov, J. A., & Crotty, S. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2013.04.003 · Cited by 103 · see citing works
Lelièvre, E., Plun-Favreau, H., Chevalier, S., Froger, J., Guillet, C., Elson, G., Gauchat, J., & Gascan, H. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101681200 · Cited by 106 · see citing works
Schmitz, J., Dahmen, H., Grimm, C., Gendo, C., Müller-Newen, G., Heinrich, P. C., & Schaper, F. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.2.848 · Cited by 92 · see citing works
Vanhoutte, F. P., Mazur, M., Voloshyn, O. I., et al. (2017) · Arthritis & Rheumatology · doi:10.1002/art.40186 · Cited by 82 · see citing works
“Gene expression of the acute-phase proteins CRP and haptoglobin, as well as YKL-40, which plays a role in inflammation and tissue remodeling (29), is under the control of the JAK/STAT pathway (30,31).”
BackgroundTanuma, N., Nakamura, K., Shima, H., & Kikuchi, K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003661200 · Cited by 79 · see citing works
Non-redundant Signal Transduction of Interleukin-6-type Cytokines
Hermanns, H. M., Radtke, S., Schaper, F., Heinrich, P. C., & Behrmann, I. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005408200 · Cited by 78 · see citing works
Loss and Dysregulation of Th17 Cells during HIV Infection
Bixler, S. L., & Mattapallil, J. J. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/852418 · Cited by 77 · see citing works
“Studies have shown that SHP2 is recruited to gp130 domain of the IL6 receptor following IL-6 signaling and dephosphorylates pSTAT3, preventing its dimerization and translocation to the nucleus [140, 141].”
BackgroundTerstegen, L., Gatsios, P., Bode, J. G., Schaper, F., Heinrich, P. C., & Graeve, L. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m904148199 · Cited by 74 · see citing works
Blanchard, F., Duplomb, L., Wang, Y., Robledo, O., Kinzie, E., Pitard, V., Godard, A., Jacques, Y., & Baumann, H. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003986200 · Cited by 66 · see citing works
Self-citationTanuma, N., Shima, H., Nakamura, K., & Kikuchi, K. (2001) · Blood · doi:10.1182/blood.v98.10.3030 · Cited by 65 · see citing works
Klausen, P. H., Pedersen, L. B., Jurlander, J., & Baumann, H. (2000) · Oncogene · doi:10.1038/sj.onc.1203707 · Cited by 65 · see citing works
“We have also demonstrated that the receptor activity and the STAT3 signal can be moderated by recruitment of protein tyrosine phosphatase 2 (SHP-2) to tyrosine 759 in the cytoplasmatic domain of gp130 (Kim et al., 1998; Kim and Baumann, 1999).”
BackgroundSelf-citationWang, Y., Robledo, O., Kinzie, E., Blanchard, F., Richards, C., Miyajima, A., & Baumann, H. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002296200 · Cited by 72 · see citing works
Self-citationWang, Y., Ripperger, J. A., Fey, G. H., Samols, D. R., Kordula, T., Wetzler, M., Etten, R. A. V., & Baumann, H. (1999) · Hepatology · doi:10.1002/hep.510300318 · Cited by 62 · see citing works
Self-citationProtein tyrosine phosphatases: their role in insulin action and potential as drug targets
Evans, J. L., & Jallal, B. (1999) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.8.2.139 · Cited by 60 · see citing works
“pathways [34-37].”
Anhuf, D., Weißenbach, M., Schmitz, J., Sobota, R. M., Hermanns, H. M., Radtke, S., Linnemann, S., Behrmann, I., Heinrich, P. C., & Schaper, F. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.5.2535 · Cited by 57 · see citing works
“A further downstream effect of SHP2 activation is the attenuation of IL-6-induced acute phase protein expression in liver cells (17, 18).”
BackgroundSHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling
Niogret, C., Birchmeier, W., & Guarda, G. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02468 · Cited by 48 · see citing works
Arnaud‐Arnould, M., Crouin, C., Déon, C., Loyaux, D., & Bertoglio, J. H. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.6.3962 · Cited by 54 · see citing works
Miura, K., Saini, S. S., Gauvreau, G. M., et al. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.4.2282 · Cited by 54 · see citing works
“It has been reported that the role of SHP2 in cytokine receptor activation is context sensitive, in some cases acting as a positive regulator of cytokine signaling (50) and sometimes acting as a negative regulator (51).”
BackgroundZorina, Y., Iyengar, R., & Bromberg, K. D. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.049841 · Cited by 50 · see citing works
Bode, J. G., Fischer, R., Häussinger, D., Graeve, L., Heinrich, P. C., & Schaper, F. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.3.1469 · Cited by 51 · see citing works
Knight, D. A., Ernst, M., Anderson, G. P., Moodley, Y. P., & Mutsaers, S. E. (2003) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(03)00095-0 · Cited by 50 · see citing works
Prasad, S., Pandey, M., Yadav, V., & Aggarwal, B. (2011) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-10-0340 · Cited by 50 · see citing works
“We also found evidence that inhibition of STAT3 activation is linked to the induction of a PTP by GA. Numerous PTPs have been implicated in STAT3 signaling, including SHP-1 (39), SHP-2 (40), TC-PTP (41), PTEN (42), PTP-1D (43), CD45 (43), and PTP-e.”
RetractedLin, H.-W., & Levison, S. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06366.x · Cited by 48 · see citing works
“Protein tyrosine phosphatases (PTP) including SHP-2, PTP1B and PTPeC, and CD45 dephosphorylate JAKs (Kim et al. 1998; Schaper et al. 1998; Tanuma et al. 2000; Irie-Sasaki et al. 2001; Myers et al. 2001).”
BackgroundBode, J. G., Schweigart, J., Kehrmann, J., Ehlting, C., Schaper, F., Heinrich, P. C., & Häussinger, D. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.1.257 · Cited by 49 · see citing works
Kang, M., & Kang, S. K. (2008) · Cell Proliferation · doi:10.1111/j.1365-2184.2008.00537.x · Cited by 58 · see citing works
“However, in other studies, the MAPK pathway is also involved in negative regulation of signal transduction through the JAK/STAT pathway (Symes et al. 1997; Kim et al. 1998; Schaper et al. 1998).”
BackgroundMolecular Basis Underlying Functional Pleiotropy of Cytokines and Growth Factors
Hirano, T. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0609 · Cited by 46 · see citing works
Sp3 is involved in the regulation of SOCS3 gene expression
Ehlting, C., Häussinger, D., & Bode, J. G. (2005) · Biochemical Journal · doi:10.1042/bj20041101 · Cited by 44 · see citing works
Baek, S., Lee, J. H., Ko, J., Lee, H., Nam, D., Lee, S.-G., Yang, W. M., Um, J., Lee, J., Kim, S.-H., et al. (2016) · Phytotherapy Research · doi:10.1002/ptr.5557 · Cited by 40 · see citing works
“Various protein tyrosine phosphatases (PTPs) have been implicated in STAT3 signaling, such as SHP-1 (Han et al., 2006), SHP-2 (Kim et al., 1998), TC-PTP (Yamamoto et al., 2002), PTEN (Sun and Steinberg, 2002), PTP-1D (Gunaje and Bhat, 2001), CD45 (Gunaje and Bhat, 2001), and PTP-ε (Tanuma et al., 2001).”
BackgroundInfluentialJenkins, B. J., Grail, D., Inglese, M., Quilici, C., Bozinovski, S., Wong, P., & Ernst, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.4.1453-1463.2004 · Cited by 43 · see citing works
“Conversely, the gp130 substitution mutation removes the phosphotyrosine residue that simultaneously provides a binding site for SHP2 and SOCS3, and therefore disrupts the capacity of SOCS3 to negatively regulate gp130-dependent signaling (35) and of SHP2 to dephosphorylate critical tyrosine residues in the gp130-JAK s…”
BackgroundFriederichs, K., Schmitz, J., Weissenbach, M., Heinrich, P. C., & Schaper, F. (2001) · European Journal of Biochemistry · doi:10.1046/j.0014-2956.2001.02586.x · Cited by 42 · see citing works
Liu, C.-Y., Huang, T.-T., Chu, P.-Y., Huang, C.-T., Lee, C.-H., Wang, W.-L., Lau, K.-Y., Tsai, W.-C., Chao, T.-I., Su, J.-C., et al. (2017) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.114 · Cited by 40 · see citing works
Mechanisms of SOCS3 Phosphorylation upon Interleukin-6 Stimulation
Sommer, U., Schmid, C., Sobota, R. M., Lehmann, U., Stevenson, N., Johnston, J., Schaper, F., Heinrich, P., & Haan, S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506008200 · Cited by 49 · see citing works
Shp2 Inhibits Proliferation of Esophageal Squamous Cell Cancer via Dephosphorylation of Stat3
Qi, C., Han, T., Tang, H., Huang, K.-N., Min, J., Li, J., Ding, X.-Y., & Xu, Z.-F. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18010134 · Cited by 35 · see citing works
“Shp2 recruitments to gp130 moderate Jak activity and consequently lead to the attenuation of Stat3 signaling [39].”
Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses
Wilmes, S., Jeffrey, P.-A., Martínez‐Fábregas, J., Hafer, M., Fyfe, P. K., Pöhler, E., Gaggero, S., López‐García, M., Lythe, G., Taylor, C., et al. (2021) · eLife · doi:10.7554/elife.66014 · Cited by 35 · see citing works
“d[S3 ⋅ D27 ⋅ pS3] dt = k3a + [S3][D27 ⋅ pS3]− k3a − [S3 ⋅ D27 ⋅ pS3] (44)”
BackgroundSH2 Domain-Containing Protein-Tyrosine Phosphatases
Neel, B. G., Chan, G., & Dhanji, S. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00098-x · Cited by 34 · see citing works
Model-driven experimental analysis of the function of SHP-2 in IL-6-induced Jak/STAT signaling
Dittrich, A., Quaiser, T., Khouri, C., Görtz, D., Mönnigmann, M., & Schaper, F. (2012) · Molecular BioSystems · doi:10.1039/c2mb05488d · Cited by 32 · see citing works
The STAT3-independent Signaling Pathway by Glycoprotein 130 in Hepatic Cells
Lai, C., Ripperger, J. A., Wang, Y., Kim, H., Hawley, R. G., & Baumann, H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.12.7793 · Cited by 32 · see citing works
Self-citationThe Shp-2 tyrosine phosphatase
Lai, L. A., Zhao, C., Zhang, E. E., & Feng, G. (2003) · Topics in current genetics · doi:10.1007/978-3-540-40035-6_14 · Cited by 31 · see citing works
Mahboubi, K., & Pober, J. S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m107542200 · Cited by 31 · see citing works
Signaling Through Gp130: Toward a General Scenario of Cytokine Action
Fukada, T., Yoshida, Y., Nishida, K., Ohtani, T., Shirogane, T., Hibi, M., & Hirano, T. (1999) · Growth Factors · doi:10.3109/08977199909103518 · Cited by 28 · see citing works
Bartoe, J. L., & Nathanson, N. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0742021.x · Cited by 24 · see citing works
“Work by Symes et al. (1997b) indicates that SHP-2 can negatively regulate the gp130-dependent induction of a VIP-luciferase reporter gene, and SHP-2 also negatively regulates the IL-6-dependent expression of acute-phase plasma proteins in hepatic cells (Kim et al., 1998; Schaper et al., 1998).”
BackgroundResultInfluentialCebo, C., Durier, V., Lagant, P., Maes, E., Florea, D., Lefebvre, T., Strecker, G., Vergoten, G., & Zanetta, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m106816200 · Cited by 26 · see citing works
ERK1/2 contributes negative regulation to STAT3 activity in HSS-transfected HepG2 cells
Tian, Z., & An, W. (2004) · Cell Research · doi:10.1038/sj.cr.7290213 · Cited by 24 · see citing works
SOCS3 negatively regulates LIF signaling in neural precursor cells
Emery, B., Merson, T. D., Snell, C., Young, K. M., Ernst, M., & Kilpatrick, T. J. (2006) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2006.01.005 · Cited by 29 · see citing works
Meisch, J. P., Vogel, R. M., Schlatzer, D., Li, X., Chance, M. R., & Levine, A. D. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.0612300 · Cited by 24 · see citing works
“In addition to dephosphorylating STAT1, SHP-2 regulates the STAT3 pathway via binding tyrosine-phosphorylated gp130 [34, 35].”
BackgroundForbes, K. A., West, G., Garside, R., Aplin, J., & Westwood, M. (2009) · Endocrinology · doi:10.1210/en.2009-0166 · Cited by 23 · see citing works
Bartoe, J. L., & Nathanson, N. (2002) · Brain Research. Molecular Brain Research · doi:10.1016/s0169-328x(02)00452-7 · Cited by 20 · see citing works
Jiao, J. (2003) · Molecular Brain Research · doi:10.1016/s0169-328x(03)00286-9 · Cited by 20 · see citing works
FAIRLIE, W. D., SOUZA, D. D., NICOLA, N. A., & BACA, M. (2003) · Biochemical Journal · doi:10.1042/bj20030104 · Cited by 20 · see citing works
Clahsen, T., Lehmann, U., Stross, C., Hermanns, H., Volkmer‐Engert, R., Schneider-Mergener, J., Heinrich, P., & Schaper, F. (2005) · Cellular Signalling · doi:10.1016/j.cellsig.2004.09.016 · Cited by 20 · see citing works
Espanel, X., Wälchli, S., Gobert, R. P., Alama, M. E., Curchod, M., Gullu-Isler, N., & van Huijsduijnen, R. H. (2001) · Endocrine · doi:10.1385/endo:15:1:019 · Cited by 19 · see citing works
Potential Involvement of FRS2 in Insulin Signaling1
Delahaye, L., Rocchi, S., & OBBERGHEN, E. V. (2000) · Endocrinology · doi:10.1210/endo.141.2.7298 · Cited by 18 · see citing works
Mahboubi, K., Kirkiles-Smith, N. C., Karras, J., & Pober, J. S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211867200 · Cited by 18 · see citing works
Noonan syndrome type I with PTPN11 3 bp deletion: Structure–function implications
Lee, W. H., Raas‐Rothschild, A., Miteva, M. A., Bolasco, G., Rein, A. J. J. T., Gillis, D., Vidaud, D., Vidaud, M., Villoutreix, B. O., & Parfait, B. (2004) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.20296 · Cited by 16 · see citing works
“gp130 signaling triggered by IL6 or leukemia inhibitory factor.(7,12,13) In the absence of an appropriate phosphoty-”
BackgroundParadis, H., & Gendron, R. L. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.23.4331 · Cited by 15 · see citing works
Durham, G. A., & Palmer, T. M. (2019) · Biochemical Society Transactions · doi:10.1042/bst20190046 · Cited by 14 · see citing works
The Negative Regulation of JAK/STAT Signaling
Murphy, J. M., Tannahill, G., Hilton, D., & Greenhalgh, C. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00064-4 · Cited by 10 · see citing works
Intragenic regulation of SOCS3 isoforms
Klepsch, O., Namer, L. S., Köhler, N., Kaempfer, R., Dittrich, A., & Schaper, F. (2019) · Cell Communication and Signaling · doi:10.1186/s12964-019-0379-6 · Cited by 11 · see citing works
Watanabe, S., Zeng, R., Aoki, Y., et al. (2001) · Blood · doi:10.1182/blood.v97.5.1266 · Cited by 10 · see citing works
Differential inhibition of IL‐6‐type cytokine‐induced STAT activation by PMA
Terstegen, L., Maassen, B. G., Radtke, S., Behrmann, I., Schaper, F., Heinrich, P. C., Graeve, L., & Gatsios, P. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01826-3 · Cited by 9 · see citing works
Regulation of Protein Synthesis by Insulin Through IRS-1
Méndez, R., Welsh, G. I., Kleijn, M., Myers, M. G., White, M. F., Proud, C. G., & Rhoads, R. E. (2001) · Progress in molecular and subcellular biology · doi:10.1007/978-3-642-56688-2_3 · Cited by 8 · see citing works
Proinflammatory Stem Cell Signaling in Cardiac Ischemia
Herrmann, J. L., Markel, T. A., Abarbanell, A. M., Weil, B. R., Wang, M., Wang, Y., Tan, J., & Meldrum, D. R. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2434 · Cited by 8 · see citing works
“SHP2 is recruited to the phosphotyrosine-759 residue of activated gp130 and is then tyrosine phosphorylated (72, 80, 123, 133).”
SH2-Domain-Containing Protein–Tyrosine Phosphatases
Neel, B. G., Gu, H., & Pao, L. I. (2003) · Elsevier eBooks · doi:10.1016/b978-012124546-7/50479-4 · Cited by 4 · see citing works
Dittrich, A., Siewert, E., & Schaper, F. (2012) · Methods in molecular biology · doi:10.1007/978-1-62703-242-1_5 · Cited by 3 · see citing works
gp130-mediated signalling as a therapeutic target
Ohtani, T., Ishihara, K., Atsumi, T., Yoshida, Y., Nishida, K., Narimatsu, M., Shirogane, T., Hibi, M., & Hirano, T. (2000) · Emerging Therapeutic Targets · doi:10.1517/14728222.4.4.459 · Cited by 2 · see citing works
“Just as SHP2 can act as a negative regulator of gp130 signals both in vivo and in vitro [65,77,78], other molecules can also participate in this negative regulation.”
Background
- Authors
- Kim, H., Hawley, T. S., Hawley, R. G., & Baumann, H.
- Affiliations
- Roswell Park Comprehensive Cancer Center (US)
- 2Oncology Gene Therapy Program, The Toronto Hospital, Toronto, Ontario M5G 2M1, Canada
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1998-03-01
- Volume
- 18
- Issue
- 3
- Pages
- 1525-1533
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC108867
- OpenAlex
- W2106938542
- Semantic Scholar
- d85db1af821fa197fbb59d25e5393b9625a35b30
- Cited by
- 119
- References
- 52
- Citations by year
- 2023: 1 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 4 · 2016: 2 · 2013: 3 · 2012: 4
- FWCI
- 6.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institutes of Health (5r01ca026122-19)
- U.S. Public Health Service
- National Cancer Institute (CA-26122)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- SHP2, gp130, hepatocytes, G-CSF receptor, chimeric receptors, STAT3, STAT1, JAK signaling, haptoglobin, receptor tyrosine phosphorylation, cytokine sensitivity, hepatoma cells
- MeSH terms
- Acute-Phase Proteins, Animals, DNA-Binding Proteins, Humans, Liver, Membrane Glycoproteins, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Tumor Cells, Cultured, Signal Transduction, Trans-Activators, Antigens, CD, Protein Tyrosine Phosphatases, Intracellular Signaling Peptides and Proteins, STAT1 Transcription Factor, STAT3 Transcription Factor, Cytokine Receptor gp130, Rats, Janus Kinase 1, Janus Kinase 2, TYK2 Kinase, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Phosphatase 2
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