Fig. 1.

Hippo signaling phosphorylates YAP and regulates its nuclear/cytoplasmic distribution. When Hippo signaling is active (e.g., in response to cell density, polarity signals, or mechanical cues) the Mst1/2 kinases, in complex with Sav1, phosphorylate and activate Lats1/2 in complex with its regulatory protein MOB1/2. In addition to Mst1/2, MAP4Ks act as alternative kinases that phosphorylate Lats1/2. In turn, Lats1/2 phosphorylates YAP on highly conserved residues (in red) located within a consensus sequence that is phosphorylated by Lats1/2 (HXRXXS). The phosphorylation of YAP at Ser-127 promotes its cytoplasmic retention, whereas phosphorylation at Ser-397 induces degradation. When the Hippo pathway is off, YAP is dephosphorylated and translocated into the nucleus where YAP binds and activates the TEAD transcription factors and stimulates the expression of multiple genes. Additional details are provided in the text