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	Protein kinases of the Hippo pathway: Regulation and substrates
	Avruch, Joseph ; Zhou, Dawang ; Zhou DW(周大旺) ; Fitamant, Julien ; Bardeesy, Nabeel ; Mou, Fan ; Barrufet, Laura Regue
	2012-09
关键词	Protein kinase Hippo Mst1/2 Mob1 Lats1/2 ndr1/2
英文摘要	The "Hippo" signaling pathway has emerged as a major regulator of cell proliferation and survival in metazoans. The pathway, as delineated by genetic and biochemical studies in Drosophila, consists of a kinase cascade regulated by cell-cell contact and cell polarity that inhibits the transcriptional coactivator Yorkie and its proliferative, anti-differentiation, antiapoptotic transcriptional program. The core pathway components are the GC kinase Hippo, which phosphorylates the noncatalytic polypeptide Mats/Mob1 and, with the assistance of the scaffold protein Salvador, phosphorylates the ndr-family kinase Lats. In turn phospho-Lats, after binding to phospho-Mats, autoactivates and phosphorylates Yorkie, resulting in its nuclear exit. Hippo also uses the scaffold protein Furry and a different Mob protein to control another ndr-like kinase, the morphogenetic regulator Tricornered. Architecturally homologous kinase cascades consisting of a GC kinase, a Mob protein, a scaffolding polypeptide and an ndr-like kinase are well described in yeast; in Saccharomyces cerevisiae, e. g., the MEN pathway promotes mitotic exit whereas the RAM network, using a different GC kinase, Mob protein, scaffold and ndr-like kinase, regulates cell polarity and morphogenesis. In mammals, the Hippo orthologs Mst1 and Mst2 utilize the Salvador ortholog WW45/Sav1 and other scaffolds to regulate the kinases Lats1/Lats2 and ndr1/ndr2. As in Drosophila, murine Mst1/Mst2, in a redundant manner, negatively regulate the Yorkie ortholog YAP in the epithelial cells of the liver and gut; loss of both Mst1 and Mst2 results in hyperproliferation and tumorigenesis that can be largely negated by reduction or elimination of YAP. Despite this conservation, considerable diversification in pathway composition and regulation is already evident; in skin, e. g., YAP phosphorylation is independent of Mst1Mst2 and Lats1Lats2. Moreover, in lymphoid cells, Mst1/Mst2, under the control of the Rap1 GTPase and independent of YAP, promotes integrin clustering, actin remodeling and motility while restraining the proliferation of naive T cells. This review will summarize current knowledge of the structure and regulation of the kinases Hippo/Mst1&2, their noncatalytic binding partners, Salvador and the Rassf polypeptides, and their major substrates Warts/Lats1&2, Trc/ndr1&2, Mats/Mob1 and FOXO. (C) 2012 Elsevier Ltd. All rights reserved.; NIH [DK17776, CA136567]; Sidney Kimmel Foundation for Cancer Research; Linda J. Verville Cancer Research Foundation; 111 Project of Education of China [B06016]; Fundamental Research Funds for the Central Universities of China [2010111079]; National Natural Science Foundation of China [81101503]; Natural Science Foundation of Fujian [2011J05096]
语种	英语
出版者	ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
内容类型	期刊论文
源URL	[http://dx.doi.org/10.1016/j.semcdb.2012.07.002]
专题	生命科学－已发表论文
推荐引用方式 GB/T 7714	Avruch, Joseph,Zhou, Dawang,Zhou DW,et al. Protein kinases of the Hippo pathway: Regulation and substrates[J],2012.
APA	Avruch, Joseph.,Zhou, Dawang.,周大旺.,Fitamant, Julien.,Bardeesy, Nabeel.,...&Barrufet, Laura Regue.(2012).Protein kinases of the Hippo pathway: Regulation and substrates..
MLA	Avruch, Joseph,et al."Protein kinases of the Hippo pathway: Regulation and substrates".(2012).

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