MST4, a new Ste20-related kinase that mediates cell growth and transformation via modulating ERK pathway

In this study, we report the cloning and characterization of a novel human Ste20-related kinase that we designated MST4 (accession number AF231012). T he 416 amino acid full-length MST4 contains an aminoterminal kinase domain, which is highly homologous to MST3 and SOK, and a unique carboxy-terminal domain. Northern blot analysis indicated that MST4 is highly expressed in p lacenta, thymus, and peripheral blood leukocytes. Wild-type but not kinase- dead MST4 can phosphorylate myelin basic protein in an in vitro kinase assa y. MST4 specifically activates ERK but not JNK or p38 MAPK in transient tra nsfected cells or in stable cell lines. Overexpression of dominant negative MEK1 or treatment with PD98059 abolishes MST4-induced ERK activity, wherea s dominant-negative Ras or c-Raf-1 mutants failed to do so, indicating MST4 activates MEK1/ERK via a Ras/Raf-1 independent pathway. HeLa and Phoenix c ell lines overexpressing wild-type, but not kinase-dead, MST4 exhibit incre ased growth rate and form aggressive soft-agar colonies. These phenotypes c an be inhibited by PD98059. These results provide the first evidence that M ST4 is biologically active in the activation of MEK/ERK pathway and in medi ating cell growth and transformation.