title: Integrin α3β1 regulates kidney collecting duct development via TRAF6-dependent K63-linked polyubiquitination of Akt.
abstract: The collecting system of the kidney develops from the ureteric bud (UB), which undergoes branching morphogenesis, a process regulated by multiple factors, including integrin-extracellular matrix interactions. The laminin (LM)-binding integrin α3β1 is crucial for this developmental program; however, the LM types and LM/integrin α3β1-dependent signaling pathways are poorly defined. We show that α3 chain-containing LMs promote normal UB branching morphogenesis and that LM-332 is a better substrate than LM-511 for stimulating integrin α3β1-dependent collecting duct cell functions. We demonstrate that integrin α3β1-mediated cell adhesion to LM-332 modulates Akt activation in the developing collecting system and that Akt activation is PI3K independent but requires decreased PTEN activity and K63-linked polyubiquitination. We identified the ubiquitin-modifying enzyme TRAF6 as an interactor with the integrin β1 subunit and regulator of integrin α3β1-dependent Akt activation. Finally, we established that the developmental defects of TRAF6- and integrin α3-null mouse kidneys are similar. Thus K63-linked polyubiquitination plays a previously unrecognized role in integrin α3β1-dependent cell signaling required for UB development and may represent a novel mechanism whereby integrins regulate signaling pathways.
authors: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors: Eugenia M
authors: EM
authors: Yazlovitskaya
authors: Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors: Hui-Yuan
authors: HY
authors: Tseng
authors: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors: Olga
authors: O
authors: Viquez
authors: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors: Tianxiang
authors: T
authors: Tu
authors: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors: Glenda
authors: G
authors: Mernaugh
authors: Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Piscataway, NJ 08854.
authors: Karen K
authors: KK
authors: McKee
authors: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors: Karen
authors: K
authors: Riggins
authors: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors: Vito
authors: V
authors: Quaranta
authors: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors: Amrita
authors: A
authors: Pathak
authors: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors: Bruce D
authors: BD
authors: Carter
authors: Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Piscataway, NJ 08854.
authors: Peter
authors: P
authors: Yurchenco
authors: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors: Arnoud
authors: A
authors: Sonnenberg
authors: Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors: Ralph T
authors: RT
authors: Böttcher
authors: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors: Ambra
authors: A
authors: Pozzi
authors: Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 Veterans Affairs Hospital, Nashville, TN 37232 roy.zent@vanderbilt.edu.
authors: Roy
authors: R
authors: Zent
mesh_terms: D000818:Animals; D039201:Integrin alpha3beta1 / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D039201:Integrin alpha3beta1; D048029:TNF Receptor-Associated Factor 6; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt