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

EM Yazlovitskaya, HY Tseng, O Viquez… - Molecular biology of …, 2015 - Am Soc Cell Biol
EM Yazlovitskaya, HY Tseng, O Viquez, T Tu, G Mernaugh, KK McKee, K Riggins…
Molecular biology of the cell, 2015Am Soc Cell Biol
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 …
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.
Am Soc Cell Biol