YAP activity is stimulated by Gα-coupled receptors but is suppressed by Gs-coupled receptors.
Major finding: YAP activity is stimulated by Gα-coupled receptors but is suppressed by Gs-coupled receptors.
Mechanism: GPCRs differentially regulate LATS1/2 kinases to alter YAP phosphorylation and function.
Impact: Activating mutations in GPCRs may promote tumorigenesis via increased YAP signaling.
Mutations in the Hippo pathway, a critical regulator of organ size, are associated with tumorigenesis. Signaling through this pathway is therefore tightly controlled, in large part via the large tumor suppressor homolog 1/2 (LATS1/2) kinases, which phosphorylate and inhibit the transcription coactivators Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) to prevent activation of growth-promoting genes. Yu and colleagues investigated whether extracellular factors modulate this pathway and showed that serum induced the dephosphorylation of YAP and TAZ proteins. This modification was associated with nuclear accumulation and stabilization of active YAP protein, and was mediated by lysophospholipid components in serum, particularly sphingosine 1-phosphophate (S1P) and lysophosphatidic acid (LPA), which has been implicated in mammary hyperplasia and tumor metastasis. LPA-induced gene expression and stimulation of cell migration and proliferation in vitro were dependent on the expression of YAP and TAZ, suggesting that these coactivators play an important role in the physiologic functions of LPA. Moreover, LPA also regulated the activity of YAP and TAZ in vivo, as these proteins were dephosphorylated and enriched in the nuclei of tumor cells in mice overexpressing the LPA receptor. This G-protein–coupled receptor (GPCR) was required for the regulation of YAP by LPA signaling; stimulation of the Gα subunits G12/13 or Gq/G11 and downstream activation of Rho GTPases resulted in suppression of LATS1/2 kinase activity and subsequent YAP dephosphorylation. In contrast, YAP activity was negatively regulated by Gs-coupled receptor agonists, including epinephrine and glucagon, which promoted YAP phosphorylation by LATS1/2. These results identify GPCRs as important modulators of Hippo-YAP signaling and suggest that inhibition of the Hippo pathway may be a useful therapeutic strategy in cancers with GPCR mutations.