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Vav proteins are necessary for correct differentiation of mouse cecal and colonic enterocytes.

ABSTRACT: In the mammalian cecum and colon, a single layer of absorptive, mature enterocytes are a crucial element of the physical barrier to the contents of the lumen. Enterocytic differentiation involves expansion of cytoplasmic cytoskeletal networks, which have been proposed to maintain structural integrity of individual cells and thus the entire epithelial barrier. We sought molecular tools to test this hypothesis in vivo, because in vitro systems displaying full intestinal epithelial differentiation have not yet been developed. Vav proteins are RhoGEFs that modulate cytoskeletal networks in immune cells. We found that Vav proteins were preferentially expressed in terminally differentiating cecal and colonic enterocytes. Loss of Vav protein expression in triple-knockout mice (Vav1(-/-);Vav2(-/-);Vav3(-/-)) resulted in defective expansion of microtubule cytoskeletons, a significant decrease in cell height and diminished expression of differentiation markers. Despite these changes, enterocytes in the triple-mutant mice did not contain measurable alterations in actin cytoskeleton, apical cell-cell junctions, nuclear position or global polarized delivery of proteins involved in terminal differentiation. Aged triple-mutant mice spontaneously developed ulcerative lesions that were, in part, a result of defective wound repair. These studies show that Vav proteins are required for enterocytic differentiation and colonic epithelial barrier integrity.

SUBMITTER: Liu JY

PROVIDER: S-EPMC2724729 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Vav proteins are necessary for correct differentiation of mouse cecal and colonic enterocytes.

Liu John Y JY Seno Hiroshi H Miletic Ana V AV Mills Jason C JC Swat Wojciech W Stappenbeck Thaddeus S TS

Journal of cell science 20090112 Pt 3

In the mammalian cecum and colon, a single layer of absorptive, mature enterocytes are a crucial element of the physical barrier to the contents of the lumen. Enterocytic differentiation involves expansion of cytoplasmic cytoskeletal networks, which have been proposed to maintain structural integrity of individual cells and thus the entire epithelial barrier. We sought molecular tools to test this hypothesis in vivo, because in vitro systems displaying full intestinal epithelial differentiation ...[more]

PMID: 19139088

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Project description:Vav proteins are guanine nucleotide exchange factors for Rho family GTPases which activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. Vav proteins contain several protein binding domains which can link cell surface receptors to downstream signaling proteins. Vav1 is expressed exclusively in hematopoietic cells and tyrosine phosphorylated in response to activation of multiple cell surface receptors. However, it is not known whether the recently identified isoforms Vav2 and Vav3, which are broadly expressed, can couple with similar classes of receptors, nor is it known whether all Vav isoforms possess identical functional activities. We expressed Vav1, Vav2, and Vav3 at equivalent levels to directly compare the responses of the Vav proteins to receptor activation. Although each Vav isoform was tyrosine phosphorylated upon activation of representative receptor tyrosine kinases, integrin, and lymphocyte antigen receptors, we found unique aspects of Vav protein coupling in each receptor pathway. Each Vav protein coprecipitated with activated epidermal growth factor and platelet-derived growth factor (PDGF) receptors, and multiple phosphorylated tyrosine residues on the PDGF receptor were able to mediate Vav2 tyrosine phosphorylation. Integrin-induced tyrosine phosphorylation of Vav proteins was not detected in nonhematopoietic cells unless the protein tyrosine kinase Syk was also expressed, suggesting that integrin activation of Vav proteins may be restricted to cell types that express particular tyrosine kinases. In addition, we found that Vav1, but not Vav2 or Vav3, can efficiently cooperate with T-cell receptor signaling to enhance NFAT-dependent transcription, while Vav1 and Vav3, but not Vav2, can enhance NFkappaB-dependent transcription. Thus, although each Vav isoform can respond to similar cell surface receptors, there are isoform-specific differences in their activation of downstream signaling pathways.

Dataset Information

Vav proteins are necessary for correct differentiation of mouse cecal and colonic enterocytes.

Publications

Vav proteins are necessary for correct differentiation of mouse cecal and colonic enterocytes.

Similar Datasets

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