The RGS-RhoGEFs control the amplitude of YAP1 activation by serum

Abstract

Actin-dependent mechanisms drive the nuclear translocation of Yap1 to enable its co-activation of transcription factors that induce pro-growth and survival programs. While Rho GTPases are necessary for the nuclear import of YAP1, the relevant Guanine Exchange Factors (GEFs) and GTPase Activating Proteins (GAPs) that connect this process to upstream signaling are not well defined. To this end, we measured the impact of expressing sixty-seven RhoGEFs and RhoGAPs on the YAP1 dependent activity of a TEAD element transcriptional reporter. Robust effects by all three members of the regulator of G-protein signaling (RGS) domain containing RhoGEFs (ArhGEF1, ArhGEF11 and ArhGEF12) prompted studies relating their known roles in serum signaling onto the regulation of Yap1. Under all conditions examined, ArhGEF12 preferentially mediated the activation of YAP1/TEAD by serum versus ArhGEF1 or ArhGEF11. Conversely, ArhGEF1 in multiple contexts inhibited both basal and serum elevated YAP1 activity through its GAP activity for Gα13. The sensitivity of such inhibition to cellular density and to low states of serum signaling supports that ArhGEF1 is a context dependent regulator of YAP1. Taken together, the relative activities of the RGS-RhoGEFs were found to dictate the degree to which serum signaling promotes YAP1 activity.

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“…Rho GTPases are necessary for the nuclear localization of YAP1, where it functions as a co‐activator of transcription factors driving the expression of genes important for proliferation and contraction. Gene silencing of ARHGEF12 in MCF7 breast cancer cells resulted in lower levels of YAP1 activation ( increased S127 phosphorylation ) and phalloidin‐stained F‐actin 56 . Moreover, activation of cofilin, a major actin cytoskeleton regulatory protein, is shown to be enhanced following TAS2R agonism, promoting F‐actin destabilization and ASM cell relaxation 57 .…”

“…Gene silencing of ARHGEF12 in MCF7 breast cancer cells resulted in lower levels of YAP1 activation (increased S127 phosphorylation) and phalloidin-stained F-actin. 56 Moreover, activation of cofilin, a major actin cytoskeleton regulatory protein, is shown to be enhanced following TAS2R agonism, promoting F-actin destabilization and ASM cell relaxation. 57 Interestingly, PKA activity is involved in the phosphorylation of large tumor suppressor kinase (LATS), enhancing its activity to inhibit YAP1 via phosphorylation of the S381 residue.…”