Upstream regulators of the Hippo pathway

The mammalian Hippo pathway plays pivotal roles in regulating organ size, stem cell pluripotency and tumorigenesis. In this pathway, the kinase Lats1/2, in complex with their regulatory subunit Mob, inhibit YAP and TAZ by a direct phosphorylation. YAP and TAZ are two main downstream effectors of the Hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. A number of modulators of the Hippo pathway have been identified via extensive genetic and biochemical analysis; however, the identity of the diffusible/extracellular signals and cell surface receptors regulating the mammalian Hippo pathway remains elusive. We have recently reported that the Hippo pathway interacts with G-proteincoupled receptor (GPCR) signaling. The activity of Lats1/2 kinases and YAP/TAZ are robustly regulated by to GPCRs and their extracellular ligands. GPCR signaling can either activate or inhibit YAP/ TAZ depending on which classes of downstream heterotrimeric G-protein are coupled with. Gα 12/13 -, Gα q/11 or Gα i/o coupled signals, such as lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), repress Lats1/2 activity, leading to dephosphorylation and activation of YAP/ TAZ. On the other hand, Gα s -coupled signals, such as epinephrine and glucagon, induce kinase activity of Lats1/2, leading to phosphorylation and inhibition of YAP/TAZ (Fig. 1). These hormones also regulate the nuclear and cytoplasmic translocation of YAP/TAZ in a manner correlating with phosphorylation. Indeed, YAP/TAZ activation is crucial in mediating gene expression, cell proliferation and cell migration induced by LPA. An independent study by Wu and colleagues has similarly demonstrated the role of LPA and S1P in YAP/TAZ regulation. Upstream regulators of the Hippo pathway