Integrins, the principal receptors that mediate cell-ECM interactions, are composed of heterodimeric transmembrane and subunits. The 18 and 8 subunits found in mammals combine in a restricted manner to form specific dimers with different ligand binding properties. 1, the most abundantly expressed integrin subunit in the kidney, binds at least 12 subunits. Its short cytoplasmic tail interacts with multiple intracellular molecules tht promote integrin- mediated adhesion, migration and signaling. The best defined of these proteins are talins and kindlins, which we and others showed are required for normal integrin function. These proteins bind to two canonical NPXY motifs found in all integrin cytoplasmic tails: talins to the membrane proximal and kindlins to the membrane distal motifs. In the last funding period, we utilized integrin beta1flox/flox mice to demonstrate that this integrin subunit s required for normal uretereic bud (UB) development, as deleting it using hoxb7cre mice resulted in severe abnormalities in branching morphogenesis. We further showed that mutating canonical NPXY motifs of the integrin 1 cytoplasmic tail also resulted in abnormal UB development. Kidneys with a Y/A mutation in both motifs (thus affecting binding of talins and kindlins) are severely dysmorphic and dysplastic, but have a significantly less severe branching defect than the UB integrin 1-null mice. Thus a key unanswered question in the field of integrin biology and kidney development is how the NPXY motifs regulate integrin function and whether they have distinct functions from each other. We propose to answer this question by testing the hypothesis that binding of talins and kindlins to specific NPYX motifs of the integrin 1 cytoplasmic tail differentially regulates integrin functions required for normal UB development. This hypothesis will be tested by the following three specific aims. 1) Determine if talin binding to the membrane proximal NPXY motif of the integrin 1 cytoplasmic tail is required for normal UB development. 2) Determine if kindlin binding to the membrane distal NPXY motif of the integrin 1 cytoplasmic tail is required for normal UB development and function. 3) Define the mechanisms whereby integrin 1 NPXY motif binding proteins regulate collecting duct cell branching morphogenesis. Completion of these aims will help define the fundamental mechanisms whereby 1 integrins regulate renal tubule formation in the context of UB development. This has implications for our understanding of both congenital renal hypoplasia/dysplasia syndromes and adult renal diseases as UB branching is a key determinant of nephron number.
We anticipate that this study will generate novel insights into the role of integrins and their binding partners, talins and kindlins in the development of the collecting system of the kidney. This knowledge is fundamental to our understanding of how the renal collecting system functions and could potentially define new etiologies for dysmorphic dysgenic kidneys in infants.
|Kang, Li; Mokshagundam, Shilpa; Reuter, Bradley et al. (2016) Integrin-Linked Kinase in Muscle Is Necessary for the Development of Insulin Resistance in Diet-Induced Obese Mice. Diabetes 65:1590-600|
|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; BÃ¶ttcher, 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-Î² 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|
|Yazlovitskaya, Eugenia M; Tseng, Hui-Yuan; Viquez, Olga et al. (2015) Integrin Î±3Î²1 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-Î² signaling in matrix-producing interstitial cells. Kidney Int 88:503-14|
|Austen, Katharina; Ringer, Pia; Mehlich, Alexander et al. (2015) Extracellular rigidity sensing by talin isoform-specific mechanical linkages. Nat Cell Biol 17:1597-606|
Showing the most recent 10 out of 61 publications