Protein kinases of the Hippo pathway: regulation and substrates.
Protein kinases of the Hippo pathway: regulation and substrates.
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DOI：
10.1016/j.semcdb.2012.07.002
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发表时间：
2012-09
影响因子：
7.3
通讯作者：
Barrufet, Laura Regue
中科院分区：
文献类型：
--
作者：
Avruch, Joseph;Zhou, Dawang;Fitamant, Julien;Bardeesy, Nabeel;Mou, Fan;Barrufet, Laura Regue
“河马”信号通路已成为后生动物细胞增殖和生存的主要调节因子。果蝇的遗传和生化研究表明，该途径由受细胞-细胞接触和细胞极性调节的激酶级联组成，抑制转录辅助激活因子yorkie及其增殖、抗分化、抗凋亡的转录程序。核心途径成分是GC激酶Hippo，它磷酸化非催化多肽Mats/Mob1，并在支架蛋白萨尔瓦多的帮助下磷酸化NDR家族的激酶Lats。反过来，磷脂与磷脂结合后，会自动激活和磷酸化约克，导致其核退出。河马还使用支架蛋白Furry和另一种Mob蛋白来控制另一种类似NDR的激酶，即形态发生调节因子三角化。在酵母中，结构上由GC、MoB蛋白、支架多肽和NDR样激酶组成的同源激酶级联通路被很好地描述；在酿酒酵母中，MEN途径促进有丝分裂退出，而RAM网络使用不同的GC激酶、MoB蛋白、支架和NDR样激酶来调节细胞的极性和形态发生。在哺乳动物中，河马同源基因Mst1和Mst2利用萨尔瓦多同源基因WW45/Sav1和其他支架来调节激酶Lats1/Lats2和ndr1/NDR2。与果蝇一样，小鼠Mst1/Mst2以冗余的方式负调控肝脏和肠道上皮细胞中的Yap；Mst1和Mst2的丢失会导致过度增殖和肿瘤发生，而YAP的减少或消除在很大程度上可以抵消这一点。尽管有这样的保守，但在通路组成和调控方面的相当大的多样性已经很明显；例如，在皮肤中，YAP的磷酸化不依赖于Mst1Mst2和Lats1Lats2。此外，在淋巴样细胞中，Mst1/Mst2在Rap1 GTPase的控制下，不依赖于YAP，促进整合素聚集、肌动蛋白重塑和运动，同时抑制幼稚T细胞的增殖。本文综述了HIPPO/Mst1&2、其非催化结合伙伴萨尔瓦多和Rassf多肽以及它们的主要底物WARTS/Lats1&2、TRC/ndr1&2、Mats/Mob1和FOXO的结构和调控的研究现状。
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 S. 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 orthologues 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 naïve 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.
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影响因子：
4.8
作者：
Creasy, CL;Ambrose, DM;Chernoff, J
通讯作者：
Chernoff, J
影响因子：
30.8
作者：
Dammann, R;Li, C;Pfeifer, GP
通讯作者：
Pfeifer, GP
影响因子：
4.8
作者：
Bichsel, SJ;Tamaskovic, R;Hemmings, BA
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Hemmings, BA
影响因子：
3.2
作者：
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通讯作者：
Kalb RG
影响因子：
3.5
作者：
Creasy, CL;Chernoff, J
通讯作者：
Chernoff, J