Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice

Dab2 null mice show ovarian epithelial growth.

“Tumors/multiple types | Uterine hyperproliferation, Ovarian epithelial growth, Increased tumor incidence”

• cites Yang et al., 2006 sourceNot checked — no full text of the source
• cites Moore et al., 2013 sourceDisputed

  The Discussion (page unavailable) says ovarian surface epithelia in Dab2-deficient mice are monolayered and intact, contrary to the claimed epithelial growth. The Results report more preneoplastic lesions in the ovaries of aged mice with a dab2-deleted genotype, but do not describe ovarian epithelial growth. (LLM, conf=0.87)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

The functions of Dab2 in macrophages were suggested to promote inflammation in brain, adipose tissue, rat spinal cord injury, and central nervous system.

“The functions of Dab2 in macrophages were suggested to promote inflammation in brain (Jokubaitis et al., 2013), adipose tissue (Adamson et al., 2016), rat spinal cord injury (Ahn et al., 2011, 2015), and central nervous system (Moon et al., 2005).”

• cites Jokubaitis et al., 2013 sourcePartly supported

  The Discussion reports that Dab2-dependent macrophage/microglial responses worsen inflammatory tissue damage in experimental autoimmune encephalomyelitis (EAE). But the study locates its EAE findings in the spinal cord, not specifically the brain; the Background mentions brain injury only when describing another study's finding of Dab2 up-regulation, not a demonstrated pro-inflammatory function there. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Adamson et al., 2016 sourceDisputed

  For the adipose-tissue clause attributed to Adamson et al., the Introduction reports that deleting Dab2 exacerbated adipose tissue inflammation in high-fat-fed mice. The Methods passage likewise says deletion of Dab2 in myeloid cells worsened that inflammation. The source therefore describes DAB2 as restraining, not promoting, inflammation in this setting. (LLM, conf=0.94)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites Ahn et al., 2011, 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The lack of more noticeable differences in the mammary glands of Dab2 null mice may be due to the compensation of other endocytic adaptors, such as Numb and Arh.

“The lack of more noticeable differences in the mammary glands of Dab2 null mice may be due to the compensation of other endocytic adaptors, such as Numb and Arh.”

• cites Tao et al., 2014 sourceSupported

Dab2 null Treg cells have no obvious phenotype in vivo.

“Immune system/Treg | No obvious phenotype in vivo; failed to suppress T cells”

• Also stated in: § Roles of Dab2 in immune cells · plain

  “However, mice with Dab2 deletion in Treg cells are healthy in appearance and do not show phenotypes related to autoimmunity defects even at 1 year of age”

• cites Jain et al., 2009 sourcePartly supported

  In Results and Discussion, Dab2 conditional-knockout mice appeared healthy, lacked overt autoimmunity, and had phenotypically similar Treg cells under unperturbed conditions. But the same section reports an in vivo defect: their Treg cells failed to moderate established colitis. Thus, 'no obvious phenotype in vivo' is supported only for the unperturbed mice, not as a general statement about Treg function in vivo. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Dab2 null mice show increased serum cholesterol.

“Liver/sinusoidal endothelial cells | Increased serum cholesterol”

• Also stated in: § Function in LDL uptake and cholesterol homeostasis · plain

  “Deletion of Dab2 gene in mice only results in a small increase of serum cholesterol level (Moore et al., 2013)”

• cites Moore et al., 2013 sourceSupported
• cites Tao et al., 2016a sourcePartly supported

  The Results report increased serum cholesterol in mice lacking both Dab2 and Arh, not in Dab2-null mice alone. The Discussion says Dab2 ablation alone has a relatively minor impact on serum cholesterol and reports increased liver cholesterol in those mice; liver cholesterol is not serum cholesterol. No page numbers are available in our copy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

The impact of Dab2 deletion on cardiac development is not notable.

“though impact of Dab2 deletion on cardiac development is not notable (Morris et al., 2002b; Moore et al., 2013).”

• cites Morris et al., 2002b sourcePartly supported

  The rescue section (page unavailable) reports that mice with Dab2 deleted from the embryo proper appeared normal, were born and survived, supporting no obvious developmental defect under that condition. It does not assess cardiac development specifically; complete Dab2 deletion instead caused early embryonic lethality, as reported in the targeting section (page unavailable). (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Moore et al., 2013 sourcePartly supported

  The Results section on conditional mutant mice reports no detectable developmental defects, and the Conclusion says Dab2 is dispensable for organ development when deletion is restricted to the embryo proper. These findings support a limited developmental impact, but the paper does not specifically assess cardiac development; constitutive deletion instead caused early embryonic lethality. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

By competing with Sos1 for binding to Grb2, Dab2 acts as a negative regulator for the Ras/MAPK pathway.

“By competing with Sos1 for binding to Grb2, Dab2 acts as a negative regulator for Ras/MAPK pathway (Xu et al., 1998; Zhou and Hsieh, 2001).”

• cites Xu et al., 1998Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Zhou and Hsieh, 2001 sourceSupported

A role of Dab2 in suppressing Ras/MAPK activation accounts for embryonic development and several physiological phenotypes observed in Dab2 null mice.

“Indeed, a role of Dab2 in suppressing Ras/MAPK activation accounts for embryonic development (Yang et al., 2009) and several physiological phenotypes observed in Dab2 null mice (Tao et al., 2014, 2016b).”

• cites Yang et al., 2009 sourcePartly supported

  The Results and Discussion (page not provided) link Dab2-mediated suppression of c-Fos to extraembryonic endoderm organization and show that eliminating c-fos partially rescues early embryonic lethality. They do not establish that Dab2 suppresses Ras/MAPK activation; the Discussion instead describes regulation of activated MAPK’s nuclear entry as an untested hypothesis and identifies an additional c-Fos-independent requirement in development. The separate claim about physiological phenotypes is cited to Tao et al., not this paper. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Tao et al., 2014, 2016bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Several mechanisms have been suggested for Dab2 involvement in the TGF-beta pathway, but their actual operation in intact animals and physiological settings has yet to be demonstrated.

“Thus, several mechanisms have been suggested for the involvement of Dab2 in TGF-beta pathway, such as receptor recycling, adapting function for Smad activation, or non-canonical TGF-beta signaling through the Ras-MAPK pathway, although the actual operation of these mechanisms in intact animals and physiological settings have yet to be demonstrated.”

• cites Hocevar et al., 2005 sourcePartly supported

  The Abstract (page unavailable) describes Dab2 as an adaptor linking TGFβ receptors to Smad activation and reports a Dab2–TAK1–JNK signaling mechanism tested in cultured cells. That supports the claim that mechanisms have been proposed without demonstration in intact animals, but the paper does not establish TGFβ receptor recycling or a specifically Ras-mediated MAPK mechanism. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Prunier and Howe, 2005 sourcePartly supported

  The introductory passage describes Dab2 as an adaptor linking TGF-β receptors to Smads, and the Discussion considers a possible Smad-independent MAPK pathway. The Discussion also says that pathway remains under investigation, while the reported TGF-β experiments use cultured cells. Our copy does not specifically propose TGF-β receptor recycling or a Ras–MAPK mechanism, or explicitly state that all the listed mechanisms await demonstration in intact animals. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Chaudhury et al., 2010 sourcePartly supported

  The paper’s Abstract describes Dab2 as a mediator of TGF-β-induced EMT and says its precise function downstream of hnRNP E1 is difficult to define. It does not identify receptor recycling, Smad activation, or Ras–MAPK signaling as proposed Dab2 mechanisms, nor does it specifically say that those mechanisms remain untested in intact animals or physiological settings. No page number is available in our copy. (LLM, conf=0.79)

  Experimental — accuracy not yet measured

In the absence of Arh, the additional loss of Dab2 greatly augments serum LDL and cholesterol levels to an extent similar to that observed in LDL receptor null mice.

“However, in the absence of Arh, the additional loss of Dab2 greatly augments serum LDL and cholesterol levels to an extent similar to that observed in LDL receptor null mice (Tao et al., 2016a).”

• cites Tao et al., 2016a sourceSupported

Dab2 modulates the non-canonical pathways of TGF-beta by suppressing Ras/MAPK activation.

“Therefore, it was concluded that Dab2 modulates the non-canonical pathways of TGF-beta by suppressing Ras/MAPK activation”

• cites Mulder, 2000 sourceNot checked — no full text of the source
• cites Moustakas and Heldin, 2005 sourceNot checked — no full text of the source
• cites Lee et al., 2007 sourceCould not verify

  The Introduction and the section ‘Direct induction of MAP kinase by TGF-b is mediated by ShcA’ describe TGF-β-induced Ras/MAPK signaling and its attenuation by ShcA mutants. The passages provided and searches for Dab2 and Disabled-2 yielded no discussion of whether Dab2 suppresses that pathway, which is the claim attributed to this source. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

Dab2 does not cooperate but complements Arh in LDL receptor endocytosis in the clearance of serum LDL particles.

“The finding leads to the conclusion that Dab2 does not cooperate but complements Arh in LDL receptor endocytosis in the clearance of serum LDL particles.”

• cites Tao et al., 2016a sourcePartly supported

  The Results report that either Dab2 or Arh can support LDLR-mediated LDL uptake in mouse cells and that having both is not additive in the same cell. The Discussion describes Dab2 as supplementary to Arh in intact mice, supporting the idea that their roles complement one another in circulating LDL clearance. But the paper does not establish the broader claim that they do not cooperate in that clearance; it calls their roles concerted. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

In cultured cells, Dab2 modulates endosomal Ras/MAPK (Erk1/2) activity by regulating the disassembly of Grb2/Sos1 complexes associated with clathrin-coated vesicles.

“In cultured cells, Dab2 modulates endosomal Ras/MAPK (Erk1/2) activity by regulating the disassembly of Grb2/Sos1 complexes associated with clathrin-coated vesicles”

• cites Xu et al., 1998Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Fehrenbacher et al., 2009 sourcePartly supported

  The “Ras Signalling on endosomes” section (page unavailable) describes endosomal Ras/MAPK signaling and reports Grb2 and mSOS on endosomes. The copy does not mention Dab2 or say that it regulates disassembly of Grb2/Sos1 complexes on clathrin-coated vesicles; searches for Dab2 and the proposed mechanism found no such passage. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites Smith et al., submittedNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Dab2 null mice show delayed mammary gland involution.

“Mammary glands/epithelia | Delayed involution”

• Also stated in: § Roles of Dab2 in mammary involution · boosted

  “The most robust phenotype of Dab2 null mammary glands is a transient delay in mammary involution (Tao et al., 2014).”

• cites Tao et al., 2014 sourceSupported

Dab2 null mice show uterine hyperproliferation.

“Tumors/multiple types | Uterine hyperproliferation, Ovarian epithelial growth, Increased tumor incidence”

• cites Yang et al., 2006 sourceNot checked — no full text of the source
• cites Moore et al., 2013 sourcePartly supported

  The Results (Characterization of dab2 conditional mutant mice; page unavailable) report an increased incidence of preneoplastic lesions, including in the uterus, in aged mice with Dab2 deletion. They do not specifically report uterine hyperproliferation, and the surviving adult mice had conditional, mosaic deletion rather than constitutive Dab2-null status. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

A suppressive activity of Dab2 was observed on the MAPK downstream effector c-Fos expression.

“Additionally, a suppressive activity of Dab2 was observed on the MAPK downstream effector, the expression of c-Fos”

• cites He et al., 2001Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Smith et al., 2001 sourceSupported
• cites Yang et al., 2009 sourceSupported

Dab2's functions in mediating polarized trafficking of cell adhesion molecules such as integrins and E-cadherin provide possible mechanisms for failure in endoderm epithelial polarity, sorting, and organization of Dab2 deleted embryos.

“Thus, its functions in mediating polarized trafficking of cell adhesion molecules such as integrins and E-cadherin provide possible mechanisms for failure in endoderm epithelial polarity, sorting, and organization of Dab2 deleted embryos”

• cites Yang et al., 2007 sourcePartly supported

  The Discussion and Figure 6 describe Dab2-dependent E-cadherin trafficking as a proposed mechanism for epithelial polarity and surface positioning; the figure links loss of polarity to disorganization of Dab2-deficient endoderm cells. The paper mentions integrins as adhesion molecules, but the passages do not establish Dab2-mediated polarized trafficking of integrins. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Moore et al., 2013 sourceSupported

Compensatory expression and partial functional redundancy by Numb and Arh have been noted in Dab2 knockout mice.

“Compensatory expression and partial functional redundancy by numb and Arh have been noted in Dab2 knockout mice (Moore et al., 2013; Tao et al., 2014, 2016a).”

• cites Moore et al., 2013 sourcePartly supported

  The Results report elevated Numb and Arh expression in Dab2-deleted E9.5 embryos, supporting compensatory expression. The Results also propose that these proteins may partly substitute for Dab2, but say that further deletion or overexpression experiments are needed to test functional rescue; partial functional redundancy was therefore suggested, not established. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Tao et al., 2014, 2016aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

LRP2/Megalin was one of the first endocytic cargos identified for the Dab2 adaptor.

“LRP2/Megalin was one of the first endocytic cargos identified for the Dab2 adaptor (Oleinikov et al., 2000; Yang et al., 2002a)”

• cites Oleinikov et al., 2000 sourceSupported
• cites Yang et al., 2002a sourceSupported

The combination of Arh and Dab2 is responsible for the majority of adaptor functions in LDLR endocytosis and LDLR-mediated cholesterol homeostasis.

“The study concludes that the combination of Arh and Dab2 is responsible for the majority of adaptor functions in LDLR endocytosis and LDLR-mediated cholesterol homeostasis.”

• cites Tao et al., 2016a sourceSupported

When Sox2-Cre is used to delete Dab2 in cre-lox conditional knockout mice to bypass its role in early embryogenesis, live mice are produced.

“When Sox2-Cre is used to delete Dab2 gene in the cre-lox conditional knockout mice to bypass the its role in early embryogenesis (Yang et al., 2002a, 2007), live mice are produced (Moore et al., 2013).”

• cites Moore et al., 2013 sourceSupported

Aged Dab2 null mice have higher frequency of tumors upon dissection, mainly in the uterus, ovary, liver, mammary gland, and colon.

“The aged Dab2 null mice have higher frequency of tumors upon dissection, observed mainly in the uterus, ovary, liver, mammary gland, and colon, similar to the previous report for the dab2 heterozygous mice (Yang et al., 2006; Moore et al., 2013).”

• cites Yang et al., 2006 sourceNot checked — no full text of the source
• cites Moore et al., 2013 sourcePartly supported

  In Results, under “Characterization of dab2 conditional mutant mice” (page not provided), the paper reports an increased incidence of preneoplastic lesions in aged mice, mainly in the uterus, ovary, mammary gland, and colon. It does not report tumors at those sites or include the liver; it says the tumor phenotypes will be reported elsewhere. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

In adipose tissues, Dab2 is expressed in pericytes attached to vascular structures.

“In adipose tissues, Dab2 is found to express in pericytes attached to the vascular structures (Tao et al., 2016b).”

• cites Tao et al., 2016b sourceSupported

No increased tumor incidence was reported in the characterization of a Dab2 conditional knockout line using Meox2-Cre.

“though no increased tumor incidence was reported in the characterization of a Dab2 conditional knockout line (using Meox2-Cre; Morris et al., 2002b).”

• cites Morris et al., 2002b sourceSupported

Another more recent Dab2 conditional line showed increases in incidence of tumors and preneoplastic lesions.

“For another Dab2 conditional line produced more recently, increases in incidence of tumors and preneoplastic lesions were noticed (Moore et al., 2013).”

• cites Moore et al., 2013 sourcePartly supported

  In Results, under “Characterization of dab2 conditional mutant mice” (page unavailable), the authors report an increased incidence of preneoplastic lesions in aged mice from their conditional line. They do not report an increased incidence of tumors; they say studies of tumor phenotypes will be reported elsewhere. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

The difference in resistance to high caloric diet-induced weight gain in Dab2-deleted mice is present only in juvenile but not mature mice.

“The remarkable difference in resistance to high caloric diet-induced weight gain of the dab2-deleted mice was present only in juvenile but not in mature mice (Tao et al., 2016b).”

• cites Tao et al., 2016b sourceSupported

Dab2 tumor suppressor function is attributed to suppressing Ras/MAPK signaling.

“The tumor suppressor functions of Dab2 have been attributed to its roles in suppressing Ras/MAPK signaling (He et al., 2001; Zhou and Hsieh, 2001)”

• cites He et al., 2001Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Zhou and Hsieh, 2001 sourceSupported

Pregnancy and lactation at early age is known to have a small protective effect against breast cancer.

“From epidemiological studies, pregnancy and lactation at early age is known to have a small protective effect against breast cancer (Kelsey and Gammon, 1991).”

• cites Kelsey and Gammon, 1991 sourceCould not verify

  No passage from our copy matched the claim. Searches for early pregnancy, age at first birth, lactation, and breastfeeding returned no passages, so the claimed protective effect cannot be verified from our copy. (LLM, conf=0.70)

  Experimental — accuracy not yet measured

Dab2 is required for adipocyte differentiation.

“Based on analyses of cell lines and primary stromal mesenchymal stem cells and cells of the adipose vascular stromal fraction, the mechanism was determined to be a requirement of Dab2 in adipocyte differentiation (Figure 4; Tao et al., 2016b).”

• cites Tao et al., 2016b sourceSupported

In pre-adipocytes, Dab2 is required to suppress Ras/MAPK activity.

“In the pre-adipocytes, Dab2 is required to suppress the activity of Ras/MAPK”

• cites Tao et al., 2016b sourceSupported

The resistance to high fat diet-induced weight gain in adipose lineage Dab2-deleted mice is adipocyte cell autonomous.

“Restricted Dab2 deletion in adipose lineage using aP2-Cre supports that this phenotype is adipocyte cell autonomous”

• cites Tao et al., 2016b sourceSupported

Dab2 tumor suppressor function is attributed to cell adhesion/migration.

“and cell adhesion/migration (Chetrit et al., 2009; Chao and Kunz, 2009; Chetrit et al., 2009; Teckchandani et al., 2009; Xie et al., 2015).”

• cites Chetrit et al., 2009 sourceNot checked — no full text of the source
• cites Chao and Kunz, 2009 sourcePartly supported

  The Results (§3.3; page not provided) show that DAB2 helps regulate focal adhesion disassembly and that combined DAB2/AP-2 knockdown inhibits cell migration. The paper does not attribute DAB2’s tumor-suppressor function to its role in adhesion or migration. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Teckchandani et al., 2009 sourcePartly supported

  The Results report that removing Dab2 inhibited HeLa cell migration on collagen IV, supporting a role in migration. But the Introduction says it is unclear whether Dab2’s roles in cancer and migration share a mechanism, and the Discussion considers an effect on adhesion unlikely to explain its migration result. The paper therefore does not establish that Dab2’s tumor-suppressor function is attributable to adhesion or migration. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Dab2 is essential for the expansion of adipocyte cell number.

“The research results suggest Dab2 is essential for the expansion of adipocyte cell number.”

• cites Tao et al., 2016b sourcePartly supported

  The Results section reports fewer adipocytes in Dab2-deficient mice fed a high-fat diet, supporting a role for Dab2 in cell-number expansion. The Discussion limits this effect to young mice and says older mice did not differ from controls in their response to the diet; the claim omits those age and diet conditions. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Dab2 is highly expressed in extraembryonic tissues (placenta) during development.

“In, Dab2 is seen highly expressed in extraembryonic tissues (placenta) during development.”

Tumor incidence in aged Dab2 null mice is relatively low, about 10%.

“Nevertheless, tumor incidence is relatively low (about 10%)”

Studies of mutant mice established that Dab2 plays multiple physiological roles through its endocytic functions and modulation of signal pathways.

“The studies of mutant mice established that Dab2 plays multiple physiological roles through its endocytic functions and modulation of signal pathways.”

Dab2 plays a role in cellular trafficking of transmembrane receptors and signaling proteins.

“cell biology studies revealed that Dab2 plays a role in cellular trafficking of a number of transmembrane receptors and signaling proteins”

More recent investigation of Dab2-deficient mice revealed several phenotypes that can be accounted for by previously suggested mechanisms.

“more recent investigation of the Dab2-deficient mice revealed several phenotypes, which can be accounted for by several previously suggested mechanisms”

The activity of Dab2 as a negative regulator of the Ras/MAPK pathway probably contributes to its tumor suppressor activity.

“Probably, the activity as a negative regulator of the Ras/MAPK pathway contributes to the tumor suppressor activity of Dab2 as well.”

Dab2 has a C-terminal proline-rich domain that mediates association with Grb2, Src, and Fyn.

“In addition, Dab2 has feature of an signaling adaptor, as the C-terminal part of the protein contains a proline-rich domain that mediates the association of Dab2 with additional proteins, such as Grb2, Src, and Fyn”

• cites Xu et al., 1998Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Through endocytosis of signaling components such as Axin or LRP6, Dab2 is suggested to play roles in regulation of the Wnt pathways.

“Through its functions in endocytosis of signaling components such as Axin or LRP6, Dab2 is also suggested to plays roles in the regulation of the Wnt pathways”

• cites Hocevar et al., 2003 sourceNot checked — no full text of the source
• cites Jiang et al., 2008, 2009, 2012Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Because the two SH3 domains of Grb2 bind competitively to both Sos1 and Dab2, expression levels and phosphorylation of Dab2 and Sos1 modulate the abundance of Sos1/Grb2 complexes.

“Since the two SH3 domains of Grb2 bind competitively to both Sos1 and Dab2, to their proline-rich motifs, expression levels and phosphorylation of Dab2 and Sos1 modulate the abundance of Sos1/Grb2 complexes.”

• cites Xu et al., 1998Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Megalin/Dab2 mediated protein re-uptake in proximal tubule cells is a likely physiological function of Dab2 in kidney.

“megalin/Dab2 mediated protein re-uptake in the proximal tubule cells is an likely physiological function of Dab2 in kidney”

The hormonal regulation of Dab2 expression in mammary epithelial cells is unique, since the expression was not seen to be significantly altered by sterol hormones in other tissues or cell types.

“The hormonal regulation of Dab2 expression in mammary epithelial cells is unique, since the expression was not seen to be significantly altered by sterol hormones in other tissues or cell types.”

Physiological phenotypes in the Dab2 conditional knockout mice have been observed in many tissues or cell types that have high Dab2 expression in wild-type mice.

“As expected, physiological phenotypes in the Dab2 conditional knockout mice have been observed in many of these tissues or cell types that have high Dab2 expression in wild-type mice”

Increased TGF-beta-stimulated Ras/MAPK activation and subsequent induction of higher expression of survival genes may explain the prolonged survival of mammary epithelial cells of Dab2-null mice during involution.

“The increased TGF-beta-stimulated Ras/MAPK activation and subsequent induction of higher expression of survival genes (Boucher et al., 2000; Balmanno and Cook, 2009) may explain the prolonged survival of mammary epithelial cells of Dab2-null mice during involution (Tao et al., 2014).”

• cites Boucher et al., 2000 sourceNot checked — no full text of the source
• cites Balmanno and Cook, 2009 sourceNot checked — no full text of the source
• cites Tao et al., 2014 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Dab2 null mice show increased tumor incidence.

“Tumors/multiple types | Uterine hyperproliferation, Ovarian epithelial growth, Increased tumor incidence”

• cites Yang et al., 2006 sourceNot checked — no full text of the source
• cites Moore et al., 2013 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

In the absence of Arh, Dab2 in liver endothelial cells regulates the expression of HMG-CoA reductase and cholesterol synthesis in hepatocytes.

“In the absence of Arh, Dab2 in liver endothelial cells regulates the expression of HMG-CoA reductase and cholesterol synthesis in hepatocytes (Tao et al., 2016a).”

• cites Tao et al., 2016a sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Deletion of Dab2 in zebrafish embryos through Cas9 mutagenesis resulted in a significant reduction in cardiomyocyte number.

“Deletion of Dab2 in zebrafish embryos through Cas9 mutagenesis resulted in a significant reduction in cardiomyocyte number (Hofsteen et al., 2016)”

• cites Hofsteen et al., 2016 sourceNot checked — no full text of the source

Through its PTB domain, Dab2 mediates attachment of cargos containing transmembrane proteins with an NPXY motif, such as LDL receptor, EGF receptor, megalin, and integrins, to clathrin coats.

“Through its PTB domain, Dab2 mediates the attachment of cargos containing transmembrane proteins with an NPXY motif, such as the LDL receptor, EGF receptor, megalin, and integrins, to clathrin coats”

• cites Mishra et al., 2002 sourceNot checked yet
• cites Morris et al., 2002a sourceNot checked — no full text of the source
• cites Bonifacino and Traub, 2003 sourceNot checked — no full text of the source

In cell culture studies, Dab2 modulates several signaling pathways.

“In cell culture studies, Dab2 also was shown to modulate several signaling pathways.”

LDL receptor family members contain NPXY motif(s) specifically recognized by Dab2.

“The members of the LDL (low density lipoprotein) receptor family contain the NPXY motif(s) specifically recognized by Dab2”

• cites Willnow et al., 1999 sourceNot checked — no full text of the source
• cites Herz et al., 2000 sourceNot checked — no full text of the source
• cites Hussain, 2001 sourceNot checked — no full text of the source

The N-terminal PTB/PID domain of Dab2 binds an NPXY motif found in a subset of cell surface receptors.

“At the N-terminus, Dab2 possesses a PTB/PID domain that can bind an NPXY (Asn-Pro-X-Tyr, X represents any amino acid) motif found in a subset of cell surface receptors (Bork and Margolis, 1995).”

• cites Bork and Margolis, 1995 sourceNot checked — no full text of the source

In cultured cells, Dab2 plays a role in the endocytosis of LDL receptor, in coordination with Arh.

“In studies using cultured cells, Dab2 was found to play a role in the endocytosis of LDL receptor, in coordination with Arh”

• cites Morris and Cooper, 2001 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Maurer and Cooper, 2006 sourceNot checked — no full text of the source

Dab2 null mice show failed cell sorting in blastocysts/primitive and extraembryonic endoderm early embryos.

“Blastocysts/primitive and extraembryonic endoderm early embryos | Failed cell sorting”

• cites Morris et al., 2002b sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Yang et al., 2002b, 2007Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Moore et al., 2013 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Numb and Arh protein levels are elevated in Dab2-deficient mammary epithelial cells.

“Indeed, Numb and Arh protein levels are elevated in Dab2-deficient mammary epithelial cells (Tao et al., 2014).”

• cites Tao et al., 2014 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

The lactating mammary gland has relatively high Dab2 expression.

“Among the mouse tissues surveyed, the lactating mammary gland has relatively high Dab2 expression (Figure 2).”

An increase in total Erk1/2 activity was observed in total embryonic lysate of E9.5 Dab2 null embryos.

“an increase in total Erk1/2 activity was observed in the total embryonic lysate of E9.5 Dab2 null embryos (Smith et al., submitted)”

• cites Smith et al., submittedNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Studies in cultured cells suggested a role of Dab2 in endocytic recycling and trafficking of integrins and thus impact cell mobility.

“Studies in cultured cells suggested a role of Dab2 in endocytic recycling and trafficking of integrins and thus impact cell mobility”

• cites Caswell et al., 2009 sourceNot checked — no full text of the source
• cites Chao and Kunz, 2009 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Chetrit et al., 2009 sourceNot checked — no full text of the source

Dab2 has a physiological role in the fine-tuning of the Ras/MAPK pathway.

“suggesting Dab2 has a physiological role in the fine-tuning of the Ras/MAPK pathway”

• cites Smith et al., submittedNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Dab2 null adipose/adipocytes/pericytes are resistant to induced adipogenesis.

“Adipose/Adipocytes/pericytes | Resistant to induced adipogenesis”

• cites Tao et al., 2016b sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Dab2 links clathrin-coated cargos containing transmembrane proteins with an NPXY motif to the myosin motor, facilitating their endocytosis and directional trafficking.

“Thus, Dab2 links clathrin-coated cargos containing transmembrane proteins with an NPXY motif to the myosin motor, facilitating their endocytosis and directional trafficking”

• cites Morris et al., 2002a sourceNot checked — no full text of the source
• cites Hasson, 2003 sourceNot checked — no full text of the source

The Dab2 proline-rich domain contains multiple stretches of poly-proline motifs that resemble those in Sos1.

“The Dab2 proline-rich domain (PRD) at C-terminus contains multiple stretches of poly-proline motifs that resemble those in Sos1, a guanine nucleotide exchange factor for and activator of Ras”

• cites Xu et al., 1998Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The C-terminus of Dab2 binds the myosin VI motor protein.

“The C-terminus binds to the myosin VI motor protein (Inoue et al., 2002; Morris et al., 2002a; Hasson, 2003; Spudich et al., 2007).”

• cites Inoue et al., 2002 sourceNot checked — no full text of the source
• cites Morris et al., 2002a sourceNot checked — no full text of the source
• cites Hasson, 2003 sourceNot checked — no full text of the source

Dab2 null Treg cells fail to suppress T cells.

“Immune system/Treg | No obvious phenotype in vivo; failed to suppress T cells”

• Also stated in: § Roles of Dab2 in immune cells · plain

  “In in vitro assay, Dab2-restricted knockout of Treg cells failed to suppress the proliferation of responder T cells.”

• cites Jain et al., 2009 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Deletion of the Dab2 gene in mice only results in a small increase of serum cholesterol level.

“Deletion of Dab2 gene in mice only results in a small increase of serum cholesterol level (Moore et al., 2013)”

• cites Moore et al., 2013 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Dab2 null mice show mild proteinuria.

“Kidney/proximal convoluted tubule epithelia | Mild proteinuria”

• Also stated in: § Roles of Dab2 in kidney: protein re-uptake · plain

  “Indeed, Dab2 null mice have a mild proteinuria (Morris et al., 2002b; Moore et al., 2013).”

• cites Morris et al., 2002b sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

• cites Moore et al., 2013 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

The redundant function of Arh with Dab2 may account for the very mild kidney functional defect in the Dab2 null mice.

“The redundant function of Arh with Dab2 may account for the very mild kidney functional defect in the Dab2 null mice (Nagai et al., 2003).”

• cites Nagai et al., 2003 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

To date, Dab2 expression has been reported to be reduced or lost in many additional cancer types, including colon, prostate, esophageal, nasopharyngeal, and head and neck.

“To date, Dab2 expression has been reported to be reduced or lost in many additional cancer types, including colon (Kleeff et al., 2002), prostate (Tseng et al., 1998), esophageal (Anupam et al., 2006), nasopharyngeal (Tong et al., 2010), and head and neck (Hannigan et al., 2010).”

• cites Kleeff et al., 2002 sourceNot checked — no full text of the source
• cites Tseng et al., 1998 sourceNot checked — no full text of the source
• cites Anupam et al., 2006 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Dab2 is not required for embryonic development of adipose tissues.

“suggesting Dab2 is not required for embryonic development of adipose tissues”

Phenotypic characterization of Dab2 null mice has revealed how endocytosis may impact physiological functions in intact animals.

“The phenotypic characterization of the Dab2 null mice has revealed how endocytosis may impact the physiological functions in intact animals (Table 1).”

The observed physiological functions can be accounted for by the cellular function of Dab2 in endocytosis: substrate uptake and modulation of signaling pathway, especially Ras/MAPK.

“So far, the observed physiological functions can be accounted for by the cellular function of Dab2 in endocytosis: substrate uptake and modulation of signaling pathway (especially Ras/MAPK pathway).”

Dab2 gene deletion was reported to affect regulatory T cell (Treg) function.

“Dab2 gene deletion was reported to affect regulatory T cell (Treg) function (Jain et al., 2009).”

• cites Jain et al., 2009 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Several subsequent reports corroborated loss or reduced Dab2 expression in human breast cancer.

“Several subsequent reports corroborated loss or a reduced Dab2 expression in human breast cancer (Sheng et al., 2000b; Bagadi et al., 2007).”

• cites Sheng et al., 2000b sourceNot checked — no full text of the source
• cites Bagadi et al., 2007 sourceNot checked — no full text of the source

The link of Dab2 to oncogenesis was first made in a differential expression screening experiment, in which a short mRNA fragment identified as DOC-2 was found lost in ovarian cancer.

“The link of Dab2 to oncogenesis was first made in a differential expression screening experiment, in which a short mRNA fragment was identified as DOC-2 (differentially expressed in ovarian cancer, known as Dab2 at a later time), and the mRNA was found lost in ovarian cancer (Mok et al., 1994).”

• cites Mok et al., 1994 sourceNot checked — no full text of the source

Dab2 tumor suppressor function is attributed to epithelial organization.

“epithelial organization (Sheng et al., 2000b; Yang et al., 2002b, 2007)”

• cites Sheng et al., 2000b sourceNot checked — no full text of the source
• cites Yang et al., 2002b sourceNot checked — no full text of the source
• cites Yang et al., 2007 sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Adipose lineage Dab2-deleted (aP2-Cre) mice have essentially the same levels of serum glucose, lipids, and other metabolites as wildtypes.

“and the adipose lineage Dab2-deleted (using aP2-Cre) mice have essentially the same levels of serum glucose, lipids, and other metabolites as wildtypes.”

• cites Tao et al., 2016b sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Redundancy with similar adaptors, especially Arh and numb expressed in the same cell types, may obscure the physiological impacts and roles of Dab2.

“Redundancy with similar adaptors, especially Arh and numb that are expressed in the same cell types, may obscure the physiological impacts and roles of Dab2.”

Dab2 was identified as a suppressed gene in carcinogen-induced mammary tumors in rodents.

“Another early support was the identification of Dab2 as a suppressed gene in carcinogen-induced mammary tumors in rodents (Schwahn and Medina, 1998).”

• cites Schwahn and Medina, 1998 sourceNot checked — no full text of the source

Induction of Dab2 expression may contribute to the protection against breast cancer risk that pregnancy and lactation may offer.

“Thus, the induction of Dab2 expression may contribute to the protection against breast cancer risk that pregnancy and lactation may offer.”

Dab2 function is required for early embryonic development.

“and its function is required for early embryonic development.”

Ras/MAPK phosphorylates PPARγ and prevents its adipogenic function in pre-adipocytes.

“which otherwise phosphorylates the adipogenic master regulator PPARγ and prevents its adipogenic function (Tao et al., 2016b).”

• cites Tao et al., 2016b sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Dab2 null mice are nearly indistinguishable from wildtype mice after birth and when fed a regular chow diet.

“Interestingly, the Dab2 null mice are nearly indistinguishable from wildtype mice after birth and when been fed a regular chow diet”

• cites Tao et al., 2016b sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Dab2 null mice are resistant to high fat diet-induced weight gain.

“In a high fat and caloric feeding experiment that was to investigate cholesterol metabolism, an unexpected observation was that the Dab2 null mice were resistant to high fat diet-induced weight gain (Tao et al., 2016b).”

• cites Tao et al., 2016b sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Dab2 is a nonessential gene following completion of development.

“Although Dab2 is a nonessential gene following completion of development”

Some additional phenotypes expected from cellular studies of Dab2 are either not found or not significant in whole mice.

“Based on the cellular study of Dab2 functions in the endocytosis of LRP1 and LRP2 (megalin), integrins, TGF-beta signaling pathway, Wnt pathway, etc, some additional phenotypes are expected, but those are either not found or not significant in whole mice.”