Structure Article Structural Basis for Autoactivation of Human Mst2 Kinase and Its Regulation by RASSF5 Lisheng Ni,1 Sheng Li,1,4 Jianzhong Yu,3 Jungki Min,1,5 Chad A. Brautigam,2 Diana R. Tomchick,2 Duojia Pan,3 and Xuelian Luo1,* 1Department of Pharmacology 2Department of Biophysics The University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA 3Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 4Present address: Biologics Department, Shanghai ChemPartner Co. Ltd., Shanghai 201203, China 5Present address: Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA *Correspondence:
[email protected] http://dx.doi.org/10.1016/j.str.2013.07.008 SUMMARY dor (Sav1), the NDR family kinases Lats1 and Lats2 (Lats1/2), and the adaptor protein Mob1. They form a central kinase The tumor-suppressive Hippo pathway controls cascade to transduce signals from cell-surface receptors tissue homeostasis through balancing cell prolifera- (Avruch et al., 2012; Hergovich, 2012). tion and apoptosis. Activation of the kinases Mst1 In the canonical Hippo kinase cascade, Mst1/2, in complex and Mst2 (Mst1/2) is a key upstream event in this with Sav1, phosphorylate and activate the Lats1/2-Mob1 com- pathway and remains poorly understood. Mst1/2 plexes, which then phosphorylate the transcriptional coactivator and their critical regulators RASSFs contain Yes-associated protein (YAP), a major downstream target of the Hippo pathway (Dong et al., 2007; Hao et al., 2008; Hong and Salvador/RASSF1A/Hippo (SARAH) domains that Guan, 2012; Huang et al., 2005; Zhao et al., 2007).