TRIP6 inhibits Hippo signaling in response to tension at adherens junctions

Abstract

The transcriptional co-activator YAP controls cell proliferation, survival, and tissue regeneration in response to changes in the mechanical environment. It is not known how mechanical stimuli such as tension are sensed and how the signal is transduced to control YAP activity. Here, we show that the LIM domain protein TRIP6 acts as part of a mechanotransduction pathway at adherens junctions to promote YAP activity by inhibiting the LATS1/2 kinases. Previous studies showed that vinculin at adherens junctions becomes activated by mechanical tension. We show that vinculin inhibits Hippo signaling by recruiting TRIP6 to adherens junctions and stimulating its binding to and inhibition of LATS1/2 in response to tension. TRIP6 competes with MOB1 for binding to LATS1/2 thereby blocking MOB1 from recruiting the LATS1/2 activating kinases MST1/2. Together, these findings reveal a novel pathway that responds to tension at adherens junctions to control Hippo pathway signaling.

TRIP6 is required for tension at adherens junctions

“…Knockdown of TRIP6 was previously reported to be associated with reduced YAP activity (Dutta et al, 2018). As many studies have linked F-actin levels and tension in the actin cytoskeleton to YAP activation (Misra and Irvine, 2018;Sun and Irvine, 2016), we wondered whether TRIP6 knockdown could reduce YAP activity even under conditions where prominent basal actin fibers were observed.…”

“…LIMD1 and TRIP6 each exhibit tension-dependent localization to AJ, where they overlap with LATS proteins and with VCL (Dutta et al, 2018;Ibar et al, 2018). To directly compare their localization, MCF10A cells were cultured under low cell density conditions, which promotes tension at junctions.…”

“…where the Ajuba LIM protein (Jub) is recruited to AJ under tension, and Jub then recruits and inhibits Warts Rauskolb et al, 2014;Razzell et al, 2018). Tensiondependent inhibition and recruitment of LATS kinases to AJ has also been observed in mammalian cells, but two different proteins have been implicated in this recruitment: LIMD1 and TRIP6 (Dutta et al, 2018;Ibar et al, 2018).…”

“…A wide variety of roles for TRIP6 have been described, including effects on tumorigenesis, cell motility, telomere function, antiapoptotic signaling, and transcription, and TRIP6 has been reported to interact with a wide variety of binding partners (Lin and Lin, 2011;Willier et al, 2011). Notably, in epithelial cell lines, TRIP6 can co-immunoprecipitate with LATS kinases, co-localize with LATS kinases at junctions, and is required for localization of LATS kinases to junctions under tension (Dutta et al, 2018). TRIP6 was recruited to junctions under tension in a Vinculin (VCL)-dependent process.…”

Novel function of TRIP6, in brain ciliogenesis

“…Their interaction partners and the cellular functions of these complexes, from actin organization/cell migration through tension sensing to signal transduction, have been elaborated in numerous cell culture experiments (e.g. Crawford et al, 1992;Schmeichel & Beckerle, 1994;Yi & Beckerle, 1998;Wang et al, 1999;Petit et al, 2000;Hirota et al, 2000;Yi et al, 2002;Gur´ianova et al, 2005;Takizawa et al, 2006;Bai et al, 2007;Hirata et al, 2008;Lin & Lin, 2011;Dutta et al, 2018).…”