Integrins are transmembrane receptors composed of ? and ? subunits that mediate the interactions between cells and ECM. In mammals, there are 18 ? and 8 ? subunits, which combine to form dimers that exhibit different ligand binding properties. Integrins are classified by these ligand binding properties into collagen, LM and RGD binding receptors. The principal LM binding integrins are ?3?1, ?6?1 and ?6?4. While specificity to ligand is mediated by the integrin extracellular domains, their transmembrane domain (TM) and cytoplasmic tail (CT) play a critical role in mediating activation of selective intracellular signaling, thus contributing to specificity of integrin function. Integrin-mediated cell interactins with LMs are critical for renal collecting system development. We previously showed that deleting the integrin ?3 subunit in the UB in mice gives a developmental phenotype and, similar to the recent findings in humans, makes mice susceptible to renal fibrosis after unilateral ureteric obstruction (UUO). By contrast, deleting the integrin ?6 or ?4 subunits did not alter UB development;but UUO caused severe tubular dilatation. Our preliminary data show that integrin ?3/?6 compound mutant mice develop significantly worse renal phenotypes than single mutants, suggesting that cooperation between integrins ?3?1 and ?6 integrins is required for development and proper function of the UB. We further showed that when collecting duct (CD) cells lacking the ?3 or the ?6 subunit were plated on the same LM, there were major differences in integrin ?3?1- and ?6?1-dependent intracellular signaling. This result indicates that the ?3 and ?6 TM/CT domains activate specific signaling pathways. These observations pose several key unanswered questions in the field of LM integrins in the kidney: how do LM integrins synergize their signaling and what are the mechanisms whereby their TM/CT domains regulate differential signaling despite binding the same ligand? We will answer these questions by testing the hypothesis that functional and structural features of the TM/CT domains of the LM integrins confer specificity of signaling required for normal UB development and function. To test this hypothesis, we will:
Aim 1) Define how the LM integrins cooperate in UB development and function.
Aim 2) Determine the mechanism whereby integrin a3 and a6 CTs regulate CD cell function.
Aim 3) Determine the structures of the individual a3, a6 TM/CT domains and of the ?3?1 and ?6?1 TM/CT heterodimers.
|Chen, Xiwu; Wang, Hongtao; Liao, Hong-Jun et al. (2014) Integrin-mediated type II TGF-? receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling. J Clin Invest 124:3295-310|
|Skrypnyk, Nataliya; Chen, Xiwu; Hu, Wen et al. (2014) PPAR* activation can help prevent and treat non-small cell lung cancer. Cancer Res 74:621-31|
|Pozzi, Ambra; Zent, Roy (2011) Extracellular matrix receptors in branched organs. Curr Opin Cell Biol 23:547-53|
|Riggins, Karen S; Mernaugh, Glenda; Su, Yan et al. (2010) MT1-MMP-mediated basement membrane remodeling modulates renal development. Exp Cell Res 316:2993-3005|
|Pozzi, Ambra; Zent, Roy (2009) Regulation of endothelial cell functions by basement membrane- and arachidonic acid-derived products. Wiley Interdiscip Rev Syst Biol Med 1:254-72|
|Wang, Shizhen Emily; Xiang, Bin; Zent, Roy et al. (2009) Transforming growth factor beta induces clustering of HER2 and integrins by activating Src-focal adhesion kinase and receptor association to the cytoskeleton. Cancer Res 69:475-82|
|Pozzi, Ambra; Zent, Roy; Chetyrkin, Sergei et al. (2009) Modification of collagen IV by glucose or methylglyoxal alters distinct mesangial cell functions. J Am Soc Nephrol 20:2119-25|
|Pozzi, Ambra; Voziyan, Paul A; Hudson, Billy G et al. (2009) Regulation of matrix synthesis, remodeling and accumulation in glomerulosclerosis. Curr Pharm Des 15:1318-33|
|Moser, Markus; Legate, Kyle R; Zent, Roy et al. (2009) The tail of integrins, talin, and kindlins. Science 324:895-9|
|Benjamin, John T; Gaston, David C; Halloran, Brian A et al. (2009) The role of integrin alpha8beta1 in fetal lung morphogenesis and injury. Dev Biol 335:407-17|
Showing the most recent 10 out of 37 publications