Integrin α3β1 regulates kidney collecting duct development via TRAF6-dependent K63-linked polyubiquitination of Akt.

Yazlovitskaya EM, Tseng HY, Viquez O, Tu T, Mernaugh G, McKee KK, Riggins K, Quaranta V, Pathak A, Carter BD, Yurchenco P, Sonnenberg A, Böttcher RT, Pozzi A, Zent R
Mol Biol Cell. 2015 26 (10): 1857-74

PMID: 25808491 · PMCID: PMC4436831 · DOI:10.1091/mbc.E14-07-1203

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.

© 2015 Yazlovitskaya et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

MeSH Terms (10)

Animals Integrin alpha3beta1 Kidney Tubules, Collecting Mice Mice, Knockout Morphogenesis Proto-Oncogene Proteins c-akt Signal Transduction TNF Receptor-Associated Factor 6 Ubiquitination

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