BACKGROUND: MST1 and MST2 are the mammalian Ste20-related protein kinases most closely related to Drosophila Hippo, a major regulator of cell proliferation and survival during development. Overexpression of MST1 or MST2 in mammalian cells is proapototic; however, little is known concerning the physiologic regulation of the endogenous MST1/MST2 kinases, their role in mammalian cell proliferation, or the identity of the MST1/MST2 substrates critical to proliferative regulation. RESULTS: We show that MST1 and MST2 activity increases during mitosis, especially in nocodazole-arrested mitotic cells, where these kinases exhibit both an increase in both abundance and activation. MST1 and MST2 also can be activated nonphysiologically by okadaic acid or H2O2. The MOBKL1A and MOBKL1B polypeptides, homologs of the Drosophila MATS polypeptide, are identified as preferred MST1/MST2 substrates in vitro and are phosphorylated in cells in an MST1/MST2-dependent manner in mitosis and in response to okadaic acid or H2O2. MST1/MST2-catalyzed MOBKL1A/MOBKL1B phosphorylation alters the ability of MOBKL1A/MOBKL1B to bind and regulate downstream targets such as the NDR-family protein kinases. Thus, MOBKL1A/MOBKL1B phosphorylation in cells promotes MOBKL1A/MOBKL1B binding to the LATS1 kinase and enables H2O2-stimulated LATS1 activation loop phosphorylation. Most importantly, replacement of endogenous MOBKL1A/MOBKL1B by a nonphosphorylatable mutant is sufficient to accelerate cell proliferation substantially by speeding progression through G1/S as well as mitotic exit. CONCLUSIONS: These results establish that MST1 and MST2 are activated in mitosis and catalyze the mitotic phosphorylation of MOBKL1A/MOBKL1B. MOBKL1A/MOBKL1B phosphorylation, in turn, is sufficient to inhibit proliferation through actions at several points in the cell cycle.
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