Coordination of cell proliferation, death, and differentiation are fundamental biological processes that are critical for a wide range of physiological and pathological conditions. During development, an increase in cell number is required to boost organ and body size; meanwhile, proper differentiation of multiple cell types will assure the appropriate function of developed organs. First discovered in Drosophila, the Hippo pathway controls organ size in diverse species. Its dysregulation may result in tumor formation or organ degeneration.Essential to the Hippo pathway is a kinase cascade, wherein MST1/2 (ortholog of Drosophila Hippo) kinases and SAV1 form a complex to phosphorylate and activate LATS1/2. LATS1/2 kinases in turn phosphorylate and inhibit the transcription co-activators YAP and TAZ, two major downstream effectors of the Hippo pathway. When dephosphorylated, YAP/ TAZ translocate into the nucleus and interact with TEAD1-4 and other transcription factors to induce expression of genes that promote cell proliferation and inhibit apoptosis.
As a critical regulator of epithelial tissue growth, the Hippo pathway is a good candidate for receiving growth inhibitory signals from cell junctions in polarized epithelial cells. Evidence that junctional complexes might signal through the Hippo pathway to inhibit cell proliferation first came from studies revealing that YAP nuclear localization and activity are inversely correlated with cell density. At low cell density YAP is enriched within the nucleus and weakly phosphorylated, whereas at high cell density YAP is predominantly cytoplasmic and strongly phosphorylated. The latter observation suggests that MST and LATS kinase activity upstream of YAP are also regulated by cell density.
YAP is phosphorylated and inhibited by the LATS tumor suppressor kinase. YAP has five HXRXXS Lats phosphorylation consensus motifs, in which phosphorylation of Ser 127 results in 14-3-3 binding and cytoplasmic retention of YAP. YAP is phosphorylated by LATS on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1δ/ε to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits β-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition. Therefore, YAP is inhibited by two mechanisms that coordinately suppress YAP oncogenic activity.