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

Abstract

In this study, we report the cloning and characterization of a novel human Ste20-related kinase that we designated MST4 (accession number AF231012). The 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 placenta, thymus, and peripheral blood leukocytes. Wild-type but not kinase-dead MST4 can phosphorylate myelin basic protein in an in vitro kinase assay. MST4 speci®cally activates ERK but not JNK or p38 MAPK in transient transfected cells or in stable cell lines. Overexpression of dominant negative MEK1 or treatment with PD98059 abolishes MST4-induced ERK activity, whereas 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 cell lines overexpressing wild-type, but not kinase-dead, MST4 exhibit increased growth rate and form aggressive soft-agar colonies. These phenotypes can be inhibited by PD98059. These results provide the ®rst evidence that MST4 is biologically active in the activation of MEK/ERK pathway and in mediating cell growth and transformation. Oncogene (2001) 20, 6559 ± 6569.

The c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress-Induced Neuronal Cell Death

“…The MST family of kinases consists of MST1, MST2, MST3, and MST4 (Taylor et al, 1996;Schinkmann and Blenis, 1997;Lin et al, 2001). Each of these proteins harbors an N-terminal kinase domain and a C-terminal regulatory domain, classifying them structurally as members of the Class II germinal center kinase family of Sterile 20-like kinases (Dan et al, 2001).…”

Germinal center kinases in immune regulation

“…[53][54][55] MST4 was identified as a novel member of the GCK family of STE20 kinases in 2001 and was found to be highly expressed in placenta, thymus and peripheral blood leukocytes. 56,57 The structures of the kinase domains have been determined yet the biological functions of GCK-III in particular remain elusive. In fact, the exact activation mechanism of GCK-III and the function of their C-terminal domains have not been clearly defined.…”

SOK1 Translocates from the Golgi to the Nucleus upon Chemical Anoxia and Induces Apoptotic Cell Death

“…Based on phylogenetic analysis, Dan et al (8) further classified these two families into two distinct subfamilies for the p21-activated protein kinases and eight subfamilies for the GCKs These proteins are implicated in a wide range of biological responses such as regulation of cell proliferation, cell death, and cytoskeleton rearrangements in response to either extracellular stimuli or various forms of cellular stress. Some family members activate known mitogen-activated protein kinase pathways (9,10), whereas for others uncertainty remains as to whether they activate these core signal transduction modules (11,12).…”