Hippo Signaling

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Search this pathway for protein information from PhosphoSitePlus^®, our expert-curated knowledge base of protein phosphorylation and other post-translational modifications.

Pathway Description:

Hippo signaling is an evolutionarily conserved pathway that controls cell proliferation, apoptosis, and organ size in response to changing cell density levels. At relative low cell density, transcription co-activators YAP and TAZ bind transcription factors to induce expression of genes that favor cell growth and proliferation. Transcription factors activated following interaction with YAP and/or TAZ include TEAD, Runx2, p73, and TBX5. Interaction with p73 follows DNA damage and may promote apoptosis; most other activated transcription factors likely activate transcription of genes favoring cell growth and proliferation. As cell density increases, interaction between membrane-bound upstream hippo pathway regulators trigger activation of cytoplasmic kinases Mst1/2 and LATS1/2. Activated Mst kinase (the eponymous Hippo in Drosophila) associates with the adaptor WW45 and activates the downstream LATS kinase, which phosphorylates YAP and TAZ. Phosphorylation of these coactivators allows binding of the cytoplasmic anchor 14-3-3 protein. Prevented from entering the nucleus, YAP and TAZ can no longer help promote transcription of genes that favor increased cell growth and proliferation. Several parts of the pathway in mammalian cells remain unclear, but are suggested by better-characterized Drosophila counterparts. Cell surface protein interactions may involve Dachsous and Fat cadherins; the mechanism of Mst activation by upstream regulators Merlin and FRMD6 (Expanded in Drosophila) also remains unclear. Kinases PKA and PAK may inhibit Merlin while activated Fat receptor may inhibit cytoplasmic Dachsous.

Selected Reviews:

• McNeill H, Woodgett JR (2010) When pathways collide: collaboration and connivance among signalling proteins in development. Nat. Rev. Mol. Cell Biol. 11(6), 404–13.
• Badouel C, Garg A, McNeill H (2009) Herding Hippos: regulating growth in flies and man. Curr. Opin. Cell Biol. 21(6), 837–43.
• Buttitta LA, Edgar BA (2007) How size is controlled: from Hippos to Yorkies. Nat. Cell Biol. 9(11), 1225–7.
• Saucedo LJ, Edgar BA (2007) Filling out the Hippo pathway. Nat. Rev. Mol. Cell Biol. 8(8), 613–21.
• Sudol M, Harvey KF (2010) Modularity in the Hippo signaling pathway. Trends Biochem. Sci. 35(11), 627–33.
• Zeng Q, Hong W (2008) The emerging role of the hippo pathway in cell contact inhibition, organ size control, and cancer development in mammals. Cancer Cell 13(3), 188–92.
• Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, Guan KL (2007) Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21(21), 2747–61.

We would like to thank Dr. Marius Sudol, Staff Scientist, Geisinger Health System, Danville, PA for contributing to this diagram.