Disabled-2 Determines Commitment of a Pre-adipocyte Population in Juvenile Mice

Tao, Wensi; Moore, Robert H.; Meng, Yue; Yeasky, Toni M.; Smith, Elizabeth; Xu, Xiang Xi

doi:10.1038/srep35947

Cited by 12 publications

(14 citation statements)

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

Section: Dab2 In the Regulation Of Cellular Signaling Pathwaysmentioning

confidence: 99%

“…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). The most prominent phenotype of Dab2 knockout mice was their striking lean body composition under a high fat and high caloric diet, although the weight of the mutant mice was indistinguishable from wild-type littermates on a regular chow.…”

Section: Roles Of Dab2 In Adipocyte Differentiationmentioning

confidence: 99%

“…The most prominent phenotype of Dab2 knockout mice was their striking lean body composition under a high fat and high caloric diet, although the weight of the mutant mice was indistinguishable from wild-type littermates on a regular chow. 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). Restricted Dab2 deletion in adipose lineage using aP2-Cre supports that this phenotype is adipocyte cell autonomous, and the adipose lineage Dab2-deleted (using aP2-Cre) mice have essentially the same levels of serum glucose, lipids, and other metabolites as wildtypes.…”

Section: Roles Of Dab2 In Adipocyte Differentiationmentioning

confidence: 99%

“…Restricted Dab2 deletion in adipose lineage using aP2-Cre supports that this phenotype is adipocyte cell autonomous, and the adipose lineage Dab2-deleted (using aP2-Cre) mice have essentially the same levels of serum glucose, lipids, and other metabolites as wildtypes. 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). In the pre-adipocytes, Dab2 is required to suppress the activity of Ras/MAPK, which otherwise phosphorylates the adipogenic master regulator PPARγ and prevents its adipogenic function (Tao et al, 2016b).…”

Section: Roles Of Dab2 In Adipocyte Differentiationmentioning

confidence: 99%

“…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). In the pre-adipocytes, Dab2 is required to suppress the activity of Ras/MAPK, which otherwise phosphorylates the adipogenic master regulator PPARγ and prevents its adipogenic function (Tao et al, 2016b). …”

Section: Roles Of Dab2 In Adipocyte Differentiationmentioning

confidence: 99%

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Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice

Tao

Moore

Smith

et al. 2016

Front. Cell Dev. Biol.

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Disabled-2 (Dab2) is a clathrin and cargo binding endocytic adaptor protein, and cell biology studies revealed that Dab2 plays a role in cellular trafficking of a number of transmembrane receptors and signaling proteins. A PTB/PID domain located in the N-terminus of Dab2 binds the NPXY motif(s) present at the cytoplasmic tails of certain transmembrane proteins/receptors. The membrane receptors reported to bind directly to Dab2 include LDL receptor and its family members LRP1 and LRP2 (megalin), growth factor receptors EGFR and FGFR, and the cell adhesion receptor beta1 integrin. Dab2 also serves as an adaptor in signaling pathways. Particularly, Dab2 facilitates the endocytosis of the Ras activating Grb2/Sos1 signaling complex, controls its disassembly, and thereby regulates the Ras/MAPK signaling pathway. Cellular analyses have suggested several diverse functions for the widely expressed proteins, and Dab2 is also considered a tumor suppressor, as loss or reduced expression is found in several cancer types. Dab2 null mutant mice were generated and investigated to determine if the findings from cellular studies might be important and relevant in intact animals. Dab2 conditional knockout mice mediated through a Sox2-Cre transgene have no obvious developmental defects and have a normal life span despite that the Dab2 protein is essentially absent in the mutant mice. The conditional knockout mice were grossly normal, though more recent investigation of the Dab2-deficient mice revealed several phenotypes, which can be accounted for by several previously suggested mechanisms. The studies of mutant mice established that Dab2 plays multiple physiological roles through its endocytic functions and modulation of signal pathways.

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Section: Dab2 In the Regulation Of Cellular Signaling Pathwaysmentioning

confidence: 99%

Section: Roles Of Dab2 In Adipocyte Differentiationmentioning

confidence: 99%

Section: Roles Of Dab2 In Adipocyte Differentiationmentioning

confidence: 99%

Section: Roles Of Dab2 In Adipocyte Differentiationmentioning

confidence: 99%

Section: Roles Of Dab2 In Adipocyte Differentiationmentioning

confidence: 99%

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Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice

Tao

Moore

Smith

et al. 2016

Front. Cell Dev. Biol.

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Phosphorylation of Dab2 is involved in inhibited VEGF‐VEGFR‐2 signaling induced by downregulation of syndecan‐1 in glomerular endothelial cell

Zhou

Wang

2020

Cell Biology International

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Disabled‐2 (Dab2) and PAR‐3 (partitioning defective 3) are reported to play critical roles in maintaining retinal microvascular endothelial cells biology by regulating VEGF‐VEGFR‐2 signaling. The role of Dab2 and PAR‐3 in glomerular endothelial cell (GEnC) is unclear. In this study, we found that, no matter whether with vascular endothelial growth factor (VEGF) treatment or not, decreased expression of Dab2 could lead to cell apoptosis by preventing activation of VEGF‐VEGFR‐2 signaling in GEnC, accompanied by reduced membrane VEGFR‐2 expression. And silencing of PAR‐3 gene expression caused increased apoptosis of GEnC by inhibiting activation of VEGF‐VEGFR‐2 signaling and membrane VEGFR‐2 expression. In our previous research, we found that the silencing of syndecan‐1 gene expression inhibited VEGF‐VEGFR‐2 signaling by modulating internalization of VEGFR‐2. And our further research demonstrated that downregulation of syndecan‐1 lead to no significant change in the expression of Dab2 and PAR‐3 both at messenger RNA and protein levels in GEnC, while phosphorylation of Dab2 was significantly increased in GEnC transfected with Dab2 small interfering RNA (siRNA) compared with control siRNA. Atypical protein kinase C (aPKC) could induce phosphorylation of Dab2, thus negatively regulating VEGF‐VEGFR‐2 signaling. And we found that decreased expression of syndecan‐1 lead to activation of aPKC, and aPKC inhibitor treatment could block phosphorylation of Dab2 in GEnC. Besides, aPKC inhibitor treatment could activate VEGF‐VGEFR‐2 signaling in GEnC transfected with syndecan‐1 siRNA in a dose‐dependent manner. In conclusion, we speculated that phosphorylation of Dab2 is involved in preventing activation of VEGF‐VEGFR‐2 signaling in GEnC transfected with syndecan‐1 siRNA. This provides a new target for the therapy of GEnC injury and kidney disease.

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