Editors' ChoiceCell Biology

Hippo Responds to GPCRs

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Sci. Signal.  21 Aug 2012:
Vol. 5, Issue 238, pp. ec218
DOI: 10.1126/scisignal.2003518

Hippo signaling is critical for determining organ size, and dysregulation of this pathway is implicated in tumorigenesis (see commentary by Codelia and Irvine). The Hippo pathway consists of the kinases MST1 and 2 (MST1/2), which activate the kinases LATS1 and 2 (LATS1/2), which in turn phosphorylate the transcriptional coactivators YAP and TAZ and lead to their retention in the cytosol. When dephosphorylated, YAP/TAZ translocate to the nucleus to induce target gene expression, which leads to cellular proliferation. Yu et al. investigated extracellular signals upstream of MST1/2 that regulated Hippo signaling. YAP became dephosphorylated and translocated to the nucleus in various cultured cell lines after the addition of serum. Lysophosphatidic acid (LPA) was the serum component that induced the activation of YAP, which was also stimulated by the lysophospholipid sphingosine 1-phosphate (S1P). Knockdown of YAP/TAZ in cultured cells inhibited the expression of some LPA target genes and LPA-induced cell migration. LPA had no effect on MST1/2 activity but inhibited the phosphorylation and activation of LATS1/2. LPA stimulates G protein–coupled receptors (GPCRs) that couple to G proteins containing Gα12 and Gα13, and receptor inhibition or knockdown blocked LPA-induced activation of YAP. In addition, knockdown of Gα12 or Gα13 or inhibition of their downstream effectors, the Rho family of guanosine triphosphatases (GTPases), prevented LPA- and S1P-induced activation of YAP. Rho GTPases regulate actin dynamics, and disruption of actin polymerization inhibited LPA- and S1P-induced YAP activation. A screen of various GPCRs showed that those that coupled to Gα12/13, Gαq/11, or Gαi/o led to YAP dephosphorylation, whereas those that coupled to Gαs, including receptors for epinephrine and glucagon, mainly induced YAP phosphorylation, which depended on cyclic adenosine monophosphate and the kinase PKA. Together, these data suggest that extracellular factors acting through GPCRs can differentially modulate Hippo signaling, depending on the G protein activated, and that Hippo signaling is required for some functions of GPCRs.

F.-X. Yu, B. Zhao, N. Panupinthu, J. L. Jewell, I. Lian, L. H. Wang, J. Zhao, H. Yuan, K. Tumaneng, H. Li, X.-D. Fu, G. B. Mills, K.-L. Guan, Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150, 780–791 (2012). [PubMed]

V. A. Codelia, K. D. Irvine, Hippo signaling goes long range. Cell 150, 669–670 (2012). [Online Journal]