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Genetic screens inDrosophilahave revealed that the serine⁄threonine kinase Hippo (Hpo) and the scaffold protein Salvador participate in a pathway that controls cell proliferation and apoptosis. Hpo most closely resembles the pro-apoptotic mammalian sterile20 kinases 1 and 2 (Mst1 and 2), and Salvador (Sav) has a human orthologue hSav (also called hWW45). | ễFEBS Journal Association of mammalian sterile twenty kinases Mst1 and Mst2 with hSalvador via C-terminal coiled-coil domains leads to its stabilization and phosphorylation Bernard A. Callus1 Anne M. Verhagen1 and David L. Vaux1 1 The Walter and Eliza Hall institute Parkville VC Australia Keywords coiled-coildomain dimerization Mst kinase phosphorylation Salvador Correspondence B. A. Callus Department of Biochemistry La Trobe University Plenty Road Bundoora VIC 3086 Australia Fax 613 9479 2467 Tel 613 9479 1669 E-mail b.callus@latrobe.edu.au Present address Department of Biochemistry La Trobe University Plenty Road Bundoora VIC 3086 Australia Received 21 May 2006 accepted 18 July 2006 doi 10.1111 j.1742-4658.2006.05427.x Genetic screens in Drosophila have revealed that the serine threonine kinase Hippo Hpo and the scaffold protein Salvador participate in a pathway that controls cell proliferation and apoptosis. Hpo most closely resembles the pro-apoptotic mammalian sterile20 kinases 1 and 2 Mst1 and 2 and Salvador Sav has a human orthologue hSav also called hWW45 . Here we show that Mst and hSav heterodimerize in an interaction requiring the conserved C-terminal coiled-coil domains of both proteins. hSav was also able to homodimerize but this did not require its coiled-coil domain. Coexpression of Mst and hSav led to phosphorylation of hSav and also increased its abundance. In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav also failed to stabilize or phosphorylate hSav whereas catalytically inactive Mst mutants that retained the ability to bind to hSav were still able to increase its abundance although they were no longer able to phosphorylate hSav. Together these results show that hSav can bind to
