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Cited by 294Cancer-related Molecular PathwaysUbiquitin and proteasome pathwaysPI3K/AKT/mTOR signaling in cancer

Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation

Open access
Feng, Jianhua, Tamaskovic, Rastislav, Yang, Zhongzhou, Brazil, Derek P., Merlo, Adrian, Hess, Daniel, Hemmings, Brian A.·2004·Journal of Biological Chemistry
DOI 10.1074/jbc.m404936200
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Abstract

The tumor suppressor p53 is commonly inhibited under conditions in which the phosphatidylinositide 3'-OH kinase/protein kinase B (PKB)Akt pathway is activated. Intracellular levels of p53 are controlled by the E3 ubiquitin ligase Mdm2. Here we show that PKB inhibits Mdm2 self-ubiquitination via phosphorylation of Mdm2 on Ser(166) and Ser(188). Stimulation of human embryonic kidney 293 cells with insulin-like growth factor-1 increased Mdm2 phosphorylation on Ser(166) and Ser(188) in a phosphatidylinositide 3'-OH kinase-dependent manner, and the treatment of both human embryonic kidney 293 and COS-1 cells with phosphatidylinositide 3'-OH kinase inhibitor LY-294002 led to proteasome-mediated Mdm2 degradation. Introduction of a constitutively active form of PKB together with Mdm2 into cells induced phosphorylation of Mdm2 at Ser(166) and Ser(188) and stabilized Mdm2 protein. Moreover, mouse embryonic fibroblasts lacking PKBalpha displayed reduced Mdm2 protein levels with a concomitant increase of p53 and p21(Cip1), resulting in strongly elevated apoptosis after UV irradiation. In addition, activation of PKB correlated with Mdm2 phosphorylation and stability in a variety of human tumor cells. These findings suggest that PKB plays a critical role in controlling of the Mdm2.p53 signaling pathway by regulating Mdm2 stability.

AI snapshot

Written from the paper’s full text.

TL;DR

PKB/Akt phosphorylates Mdm2 at Ser166 and Ser188, inhibiting Mdm2 self-ubiquitination and stabilizing Mdm2, which in turn down-regulates p53. This identifies a mechanism by which PI3K/PKB survival signaling controls the Mdm2–p53 pathway.

Key findings

  • PKB phosphorylated Mdm2 at Ser166 and Ser188; Ser188 was identified as a novel site, and the authors failed to detect phosphorylation on Ser186. Phosphorylation of wild-type GST-Mdm2 completely abolished self-ubiquitination, whereas S166A or S188V mutants were only partially inhibited; S166D, S188D, and S166D/S188D Asp mutants were poorly ubiquitinated.
  • IGF-1 increased Mdm2 phosphorylation at Ser166 and Ser188 in HEK293 cells in a PI3K-dependent manner, and LY-294002 treatment led to proteasome-mediated Mdm2 degradation in HEK293 and COS-1 cells; MG132 delayed this effect.
  • Constitutively active PKB co-transfection increased Mdm2 phosphorylation at Ser166/Ser188 and stabilized GFP-Mdm2; S166D/S188D mutants were stable even without MG132, and Mdm2 ubiquitination was reduced in the double mutant.
  • Pkbα−/− MEFs showed reduced Mdm2 protein, increased p53 and p21Cip1, and elevated apoptosis after UV irradiation; up to 60% of wild-type MEFs arrested in G1, whereas Pkbα−/− cells showed only a compromised 50% temporary G1 arrest and most underwent apoptotic death. PTEN-deficient LNCaP and U87MG cells had high PKB Ser473 phosphorylation with increased Mdm2 and Ser166/Ser188 phosphorylation.

Methods

  • In vitro PKB kinase assays and Mdm2 self-ubiquitination assays used GST-Mdm2 wild type and mutants, recombinant ΔPH-PKBα, E1 ubiquitin-activating enzyme, GST-UbcH5, and 32P-labeled GST-ubiquitin.
  • Cell experiments used HEK293, COS-1, and MEFs from Pkbα+/+ and Pkbα−/− E13.5 embryos, with transfections, immunoprecipitation, immunoblotting, and immunofluorescence; treatments included IGF-1, LY-294002, MG132, and cycloheximide.
  • Cell cycle and death analysis used BrdUrd labeling, UV-C irradiation, propidium iodide staining, and flow cytometry; human tumor cell lines were analyzed by immunoblotting and immunostaining.

Limitations

  • The paper states that how PKB phosphorylation affects Mdm2 self-ubiquitination remains to be elucidated; it proposes a possible conformational change but notes this model has yet to be tested experimentally.
  • The paper states that the reason for disparity in Mdm2 subcellular localization is not clear; Ser188 phosphorylation was not analyzed in mouse MEFs because the antibody likely cannot detect it due to sequence divergence, and the physiological relevance of Ser186 phosphorylation requires further investigation.
  • Evident from the text: many conclusions rely on in vitro reconstitution and overexpression in cell lines, and the tumor cell line data are correlative rather than causal.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1074/jbc.m404936200

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 29 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Cells Lacking PKB␣ Display Decreased Mdm2 Protein Levels and Increased Susceptibility to UV-induced Apoptosis-To con-

    Subcellular localization of endogenous Mdm2 was mainly in the nucleus in both LNCaP and LN215 cell lines.

    “the subcellular localization of endogenous Mdm2 was observed mainly in the nucleus in both cell lines (Fig. 6, B and C)”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Abstract

    Introduction of constitutively active PKB together with Mdm2 into cells stabilized Mdm2 protein.

    “Introduction of a constitutively active form of PKB together with Mdm2 into cells induced phosphorylation of Mdm2 at Ser 166 and Ser 188 and stabilized Mdm2 protein.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    MEFs lacking PKBα displayed increased p53 levels.

    “with a concomitant increase of p53 and p21 Cip1”
    Quote in the paperSubstantial claim
  • Findingown data
    § Cells Lacking PKB␣ Display Decreased Mdm2 Protein Levels and Increased Susceptibility to UV-induced Apoptosis-To con-

    Upon UV-C radiation, up to 60% of wild-type MEFs were arrested in G1 phase for the whole period of examination.

    “Upon treatment with UV-C radiation, a large proportion (up to 60%) of the wild-type MEFs were arrested in G 1 phase of cell cycle for the whole period of examination.”
    Quote in the paperSubstantial claim
  • Findingcitation
    § Cell Cycle and Cell Death Analysis-Exponentially growing

    The region surrounding Ser166 and Ser188 in human Mdm2 conforms to a consensus sequence motif for PKB phosphorylation, RXRXX(S/T).

    “The region surrounding Ser 166 and Ser 188 in human Mdm2 conforms to a consensus sequence motif for PKB phosphorylation, i.e.RXRXX(S/T) (36).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Alessi, 1996, FEBS Lett. source

      Not checked in the free run.

  • May combine two claims. 22
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Findingown data
    § Effect of Phosphorylation on Mdm2 Self-ubiquitination-We identified two major phosphorylation sites of Mdm2 on Ser

    The level of GFP-Mdm2 expression was lower in mock or KD-PKBα-transfected cells but remained high in m/p-PKBα-transfected cells.

    “Significantly, the level of GFP-Mdm2 expression was lower in the mock or KD-PKB␣-transfected cells but remained high in the m/p-PKB␣-transfected cells (Fig. 3A, left panel).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Effect of Phosphorylation on Mdm2 Self-ubiquitination-We identified two major phosphorylation sites of Mdm2 on Ser

    Wild-type GFP-Mdm2 was rapidly degraded in the absence of MG132 but markedly accumulated in the presence of MG132.

    “wild-type GFP-Mdm2 (WT) was rapidly degraded in the absence of MG132 but markedly accumulated in the presence of this inhibitor.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Effect of Phosphorylation on Mdm2 Self-ubiquitination-We identified two major phosphorylation sites of Mdm2 on Ser

    Endogenous Mdm2 protein levels in HEK293 and COS-1 cells declined rapidly in LY-294002-treated cells, and this effect was significantly delayed by MG132.

    “The level of Mdm2 protein declined rapidly in LY-294002-treated cells, and this effect was significantly delayed by treating cells with the proteasome inhibitor MG132.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: LY-294002 specifically inhibits PI3K in the cells used.

  • May combine two claims.

    Findingown data
    § Effect of Phosphorylation on Mdm2 Self-ubiquitination-We identified two major phosphorylation sites of Mdm2 on Ser

    Ubiquitination of Mdm2 accumulated in wild-type GFP-Mdm2 and HA-ubiquitin co-transfected HEK293 cells but was significantly reduced in GFP-Mdm2 S166D/S188D and HA-ubiquitin-transfected cells.

    “ubiquitination of Mdm2 accumulated in wild-type GFP-Mdm2 and HA-ubiquitin co-transfected HEK293 cells but was significantly reduced in GFP-Mdm2 S166D/S188D and HAubiquitin-transfected cells.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The S166D and S188D substitutions mimic phosphorylation at Ser166 and Ser188.

  • May combine two claims. The quote only partly states this claim.

    Findingown data
    § DISCUSSION

    Mdm2 is phosphorylated by activated PKB at Ser166 and Ser188, and Ser188 is a novel PKB phosphorylation site.

    “In this paper two PKB phosphorylation sites on Mdm2 were identified (Ser 166 and Ser 188 ), and Ser 188 is novel.”
    • Also stated in: § DISCUSSION · boosted
      “our results demonstrate that Mdm2 can be phosphorylated by activated PKB at Ser 166 and Ser 188 .”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Effect of Phosphorylation on Mdm2 Self-ubiquitination-We identified two major phosphorylation sites of Mdm2 on Ser

    Reduction of Mdm2 protein levels in mock and KD-PKBα-transfected cells was reversed upon MG132 treatment and reached a similar level to m/p-PKBα-transfected cells.

    “the reduction of Mdm2 protein levels in both mock and KD-PKB␣-transfected cells was reversed upon MG132 treatment and reached a similar level to that of the m/p-PKB␣transfected cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Effect of Phosphorylation on Mdm2 Self-ubiquitination-We identified two major phosphorylation sites of Mdm2 on Ser

    Levels of GFP-Mdm2 were markedly decreased in mock or KD-PKBα-cotransfected cells but remained relatively high in m/p-PKBα co-transfected cells over time.

    “Levels of GFP-Mdm2 were markedly decreased in mock or KD-PKB␣-cotransfected cells but remained relatively high in m/p-PKB␣ co-transfected cells over time (Fig. 3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Cells Lacking PKB␣ Display Decreased Mdm2 Protein Levels and Increased Susceptibility to UV-induced Apoptosis-To con-

    PTEN-deficient cell lines LNCaP and U87MG exhibited high levels of PKB phosphorylation on Ser473, with a concomitant increase in Mdm2 protein level and its phosphorylation on Ser166 and Ser188.

    “the PTEN-deficient cell lines LNCaP and U87MG exhibited high levels of PKB phosphorylation on Ser 473 , with a concomitant increase in Mdm2 protein level and its phosphorylation on Ser 166 and Ser 188 .”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Effect of Phosphorylation on Mdm2 Self-ubiquitination-We identified two major phosphorylation sites of Mdm2 on Ser

    IGF-1 stimulation caused a dramatic increase in phosphorylation on Mdm2 residues Ser166 and Ser188, maintained for 30 min.

    “After IGF-1 stimulation a dramatic increase in phosphorylation on Mdm2 residues Ser 166 and Ser 188 was observed, and a relatively high level of phosphorylation was maintained for the 30-min duration of the experiment (Fig. 2B).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IGF-1 activates the PI3K/PKB pathway in HEK293 cells.

  • May combine two claims.

    Findingcitation
    § DISCUSSION

    Flanking sequences of Ser166 are also conserved in mouse (Ser163), dog (Ser166), and zebrafish (Ser146) but not in Xenopus.

    “The flanking sequences of Ser 166 are also conserved in mouse (Ser 163 ), dog (Ser 166 ), and zebrafish (Ser 146 ) but not in Xenopus (13,14).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Momand, 2000, Gene (Amst.) source

      Not checked in the free run.

    • cites [14] Prives, 1998, Cell source

      Not checked in the free run.

  • May combine two claims.

    Findingown data
    § DISCUSSION

    Both endogenous Mdm2 and transfected Mdm2 were exclusively located in the nucleus independent of phosphorylation status of Mdm2.

    “both endogenous Mdm2 (Fig. 5A and Fig. 6, B and C) and transfected Mdm2 (31,51,60) were exclusively located in the nucleus independent of phosphorylation status of Mdm2.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31] Mayo, 2001, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

    • cites [51] Blattner, 2002, Mol. Cell. Biol. source

      Not checked in the free run.

    • cites [60] Ashcroft, 2002, Oncogene source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data
    § Effect of Phosphorylation on Mdm2 Self-ubiquitination-We identified two major phosphorylation sites of Mdm2 on Ser

    The Ser(P)166 and Ser(P)188 antibodies specifically detected phosphorylation of Mdm2 by PKB at Ser166 and Ser188, respectively.

    “These results suggest that each phospho antibody specifically detected phosphorylation of Mdm2 by PKB at Ser 166 and Ser 188 , respectively.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Cells Lacking PKB␣ Display Decreased Mdm2 Protein Levels and Increased Susceptibility to UV-induced Apoptosis-To con-

    Elevated PKB activity via amplification of PI3K and PKB genes, mutational loss of PTEN, or activation of oncogenic receptor tyrosine kinase is a common feature of many human cancers.

    “Elevated PKB activity via amplification of PI3K and PKB genes, mutational loss of PTEN, or activation of oncogenic receptor tyrosine kinase is a common feature of many human cancers (1,4,43).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Datta, 1999, Genes Dev. source

      Not checked in the free run.

    • cites [4] Brazil, 2001, Trends Biochem. Sci. source

      Not checked in the free run.

    • cites [43] Testa, 2001, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Abstract

    Mdm2 harbors self- and p53-specific E3 ubiquitin ligase activity within its C-terminal RING finger domain, which mediates p53 ubiquitination and rapid degradation by the 26 S proteasome.

    “Mdm2 harbors a self-and p53specific E3 ubiquitin ligase activity within its evolutionarily conserved C-terminal RING finger domain, which mediates p53 ubiquitination and rapid degradation by the 26 S proteasome (20,21).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Honda, 1999, EMBO J. source

      Not checked in the free run.

    • cites [21] Fang, 2000, J. Biol. Chem. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Mdm2 can be phosphorylated by PKB in vitro at Ser166 and Ser186, and this phosphorylation promotes nuclear entry of Mdm2.

    “Indeed, it has been reported that Mdm2 could be phosphorylated by PKB in vitro at Ser 166 and Ser 186 , and this phosphorylation promotes the nuclear entry of Mdm2 (31,32).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Mayo, 2001, Proc. Natl. Acad. Sci. U. S. A. source

      Not checked in the free run.

    • cites [32] Zhou, 2001, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Cells Lacking PKB␣ Display Decreased Mdm2 Protein Levels and Increased Susceptibility to UV-induced Apoptosis-To con-

    Activation of PKB leads to phosphorylation of Mdm2 and plays an essential role in regulating Mdm2 stability in human tumor cells.

    “These data suggest that activation of PKB leads to the phosphorylation of Mdm2 and plays an essential role in regulating Mdm2 stability in human tumor cells.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation
    § Abstract

    In normal unstressed cells, p53 is unstable with a half-life of less than 20 min and is kept at very low cellular levels by continuous degradation mediated largely by Mdm2.

    “In normal unstressed cells, p53 is an unstable protein with a half-life of less than 20 min, which is kept at very low cellular levels because of continuous degradation mediated largely by Mdm2”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (13)(14)(15)(16)(17)(18)

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Effect of Phosphorylation on Mdm2 Self-ubiquitination-We identified two major phosphorylation sites of Mdm2 on Ser

    Transfected GFP-Mdm2 is a labile protein target for degradation, and PKB phosphorylation is required for protecting Mdm2 from proteasome-dependent destruction, increasing Mdm2 stability.

    “These data suggested that transfected GFP-Mdm2 is a labile protein that is a target for degradation (20,21) and, furthermore, that PKB phosphorylation is required for protecting Mdm2 from proteasome-dependent destruction, thus increasing Mdm2 stability.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Honda, 1999, EMBO J. source

      Not checked in the free run.

    • cites [21] Fang, 2000, J. Biol. Chem. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    p53-mediated apoptosis is inhibited under conditions in which the PI3K/PKB pathway is activated.

    “Several recent studies show that p53-mediated apoptosis is inhibited under conditions in which the PI3K/PKB pathway is activated (7)(8)(9)(10)(11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (7)(8)(9)(10)(11)

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Abstract

    PKB-dependent phosphorylation of Mdm2 leads to increased Mdm2 stability and consequent down-regulation of p53.

    “Thus, our results suggest that PKBdependent phosphorylation of Mdm2 leads to the increase of Mdm2 stability and a consequent down-regulation of p53.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Effect of Phosphorylation on Mdm2 Self-ubiquitination-We identified two major phosphorylation sites of Mdm2 on Ser

    Phosphorylation of Mdm2 at Ser166 and Ser188 by PKB regulates Mdm2 protein stability, probably via inhibition of proteasome-mediated degradation.

    “These results indicate that phosphorylation of Mdm2 at Ser 166 and Ser 188 by PKB regulates Mdm2 protein stability, probably via inhibition of proteasome-mediated degradation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The S166D and S188D substitutions mimic phosphorylation at Ser166 and Ser188.

  • May combine two claims.

    Interpretationreasoning
    § DISCUSSION

    The presence of conserved sequences around Ser188 and Ser166 argues in favor of a functional role for this region, presumably via phosphorylation.

    “The presence of conserved sequences argues in favor of a functional role for this region, presumably via phosphorylation, and this has been demonstrated in human and mouse species.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § DISCUSSION

    The above data support a physiological role for PKB in the regulation of Mdm2-p53 signaling and reveal a novel mechanism of PKB-induced cellular transformation that may contribute to tumorigenesis.

    “The above data support a physiological role for PKB in the regulation of Mdm2⅐p53 signaling and reveal a novel mechanism of PKB-induced cellular transformation that may contribute to tumorigenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation
    § DISCUSSION

    Activation of PKB promotes translocation of PKB to the nucleus and phosphorylates Mdm2 in the nuclear compartment.

    “Our data suggest that activation of PKB promotes translocation of PKB to the nucleus (5,6) and phosphorylates Mdm2 in the nuclear compartment.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Andjelkovic, 1997, J. Biol. Chem. source

      Not checked in the free run.

    • cites [6] Meier, 1997, J. Biol. Chem. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Previous reports indicated survival signals positively regulate Mdm2 and lead to stabilization of the protein.

    “Previous reports have indicated that survival signals positively regulate Mdm2 and lead to stabilization of the protein (54 -57).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [54] Skorski, 1997, EMBO J. source

      Not checked in the free run.

    • cites [55] Pan, 1999, Cancer Res.

      Not checked in the free run.

    • cites [56] Goetz, 2001, Cancer Res.

      Not checked in the free run.

    • cites [57] Bardos, 2004, Mol. Cell. Biol. source

      Not checked in the free run.

25 of 25

  • The paper relies on this without support.

    The S166D and S188D substitutions mimic phosphorylation at Ser166 and Ser188.

    “Three Asp mutants (GST-Mdm2 S166D , GST-Mdm2 S188D , and GST-Mdm2 S166D/S188D ) were also generated and tested in this in vitro ubiquitination assay.”
    “Substitution of Ser 166 to Asp (GFP-Mdm2 S166D ) and Ser 188 to Asp (GFP-Mdm2 S188D ) resulted in increased Mdm2 stability even in the absence of MG132.”

  • The paper relies on this without support.

    LY-294002 specifically inhibits PI3K in the cells used.

    “The IGF-1-induced phosphorylation of Mdm2 was suppressed by pretreatment with 50 M LY-294002, an inhibitor of PI3K (Fig. 2B).”
    “The level of Mdm2 protein declined rapidly in LY-294002-treated cells”

  • The paper relies on this without support.

    IGF-1 activates the PI3K/PKB pathway in HEK293 cells.

    “Stimulation of human embryonic kidney 293 cells with insulin-like growth factor-1 increased Mdm2 phosphorylation on Ser 166 and Ser 188 in a phosphatidylinositide 3-OH kinase-dependent manner”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • AKT-mediated stabilization of MDM2 may partly account for the anti-apoptotic effect of PI3K-AKT signaling.

    “This may be partly due to AKT-dependent stabilization of MDM2 (Refs 125,126).”

    From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [125]

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.

  • Figure 5 legend lists a Ser188 analysis the text says was not done

    Minor

    The results state that Ser188 phosphorylation was not analyzed in the mouse cells, but the Figure 5B legend says those cell lysates were immunoblotted with the Ser(P)188 antibody.

  • Ser188 sequence does not match the stated PKB consensus motif

    Minor

    The stated RXRXX(S/T) motif requires an arginine three residues before the phosphorylated serine. The listed sequence around Ser188 has lysine, not arginine, at that position (Lys185).

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 6

  1. Hong, 1999, Cancer Res., 59, 2847
  2. Moll, 2003, Mol. Cancer Res., 1, 1001
  3. Mayo, 1997, Cancer Res., 57, 5013
  4. Hjerrild, 1999, Biochem. J., 15, 347
  5. Pan, 1999, Cancer Res., 59, 2064
  6. Goetz, 2001, Cancer Res., 61, 7635

Cited by

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Related

Authors
Feng, J., Tamaskovic, R., Yang, Z., Brazil, D. P., Merlo, A., Hess, D., & Hemmings, B. A.
Affiliations
  • Friedrich Miescher Institute (CH)
  • University of Basel (CH)
Corresponding author
Hemmings, Brian A.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2004-08
Volume
279
Issue
34
Pages
35510-35517
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m404936200
OpenAlex
W2015432978
Semantic Scholar
aea5e1e7e26fa43df9b4517dbb339036ec5fdfc6
Cited by
294
References
61
Citations by year
2025: 3 · 2024: 11 · 2023: 6 · 2022: 14 · 2021: 5 · 2020: 8 · 2019: 6 · 2018: 14 · 2017: 13 · 2016: 9 · 2015: 15 · 2014: 6 · 2013: 14 · 2012: 18
FWCI
10.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
MDM2, p53, Akt/protein kinase B, phosphatidylinositol 3-kinase, protein phosphorylation, proteasomal degradation, insulin-like growth factor I, p21, apoptosis, UV irradiation, tumor suppressor regulation
MeSH terms
Animals, Cell Line, Enzyme Stability, Humans, Nuclear Proteins, Phosphorylation, Proto-Oncogene Proteins, Ubiquitins, Signal Transduction, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Mice, Knockout, Phosphatidylinositol 3-Kinases, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-akt, Mice, Proto-Oncogene Proteins c-mdm2

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