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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Hoshizaki, Deborah K
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Gewin, Leslie; Zent, Roy; Pozzi, Ambra (2016) Progression of chronic kidney disease: too much cellular talk causes damage. Kidney Int :
Haake, Scott M; Li, Jiannong; Bai, Yun et al. (2016) Tyrosine Kinase Signaling in Clear Cell and Papillary Renal Cell Carcinoma Revealed by Mass Spectrometry-Based Phosphotyrosine Proteomics. Clin Cancer Res :
Borza, Corina M; Su, Yan; Tran, Truc-Linh et al. (2016) Discoidin domain receptor 1 kinase activity is required for regulating collagen IV synthesis. Matrix Biol :
Theodosiou, Marina; Widmaier, Moritz; Böttcher, Ralph T et al. (2016) Kindlin-2 cooperates with talin to activate integrins and induces cell spreading by directly binding paxillin. Elife 5:e10130
Nlandu Khodo, Stellor; Neelisetty, Surekha; Woodbury, Luke et al. (2016) Deleting the TGF-β receptor in proximal tubules impairs HGF signaling. Am J Physiol Renal Physiol 310:F499-510
Elias, Bertha C; Das, Amrita; Parekh, Diptiben V et al. (2015) Cdc42 regulates epithelial cell polarity and cytoskeletal function during kidney tubule development. J Cell Sci 128:4293-305
Keller, Birgit; Mühlenkamp, Melanie; Deuschle, Eva et al. (2015) Yersinia enterocolitica exploits different pathways to accomplish adhesion and toxin injection into host cells. Cell Microbiol 17:1179-204
Yazlovitskaya, Eugenia M; Tseng, Hui-Yuan; Viquez, Olga et al. (2015) Integrin α3β1 regulates kidney collecting duct development via TRAF6-dependent K63-linked polyubiquitination of Akt. Mol Biol Cell 26:1857-74
Borza, Corina M; Chen, Xiwu; Zent, Roy et al. (2015) Cell Receptor-Basement Membrane Interactions in Health and Disease: A Kidney-Centric View. Curr Top Membr 76:231-53
Neelisetty, Surekha; Alford, Catherine; Reynolds, Karen et al. (2015) Renal fibrosis is not reduced by blocking transforming growth factor-β signaling in matrix-producing interstitial cells. Kidney Int 88:503-14

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