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Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis, and stem cell self renewal. In addition, dysregulation of the Hippo pathway contributes to cancer development. Core 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. The Hippo pathway is involved in cell contact inhibition, and its activity is regulated at multiple levels: Mst1/2 and LATS1/2 are regulated by upstream molecules such as Merlin, KIBRA, RASSFs, and Ajuba; 14-3-3, α-catenin, AMOT, and ZO-2 retain YAP/ TAZ in the cytoplasm, adherens junctions, or tight junctions by binding; Mst1/2 and YAP/ TAZ phosphorylation and activity are modulated by phosphatases; Lats1/2 and YAP/TAZ stability are regulated by protein ubiquitination; and LATS1/2 activity is also regulated by the cytoskeleton. Despite extensive study of the Hippo pathway in the past decade, the exact nature of extracellular signals and membrane receptors regulating the Hippo pathway remains elusive.
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We would like to thank Prof. Kun-Liang Guan, University of California, San Diego, CA for contributing to this diagram.
created November 2010
revised December 2012