The survival kinase Mirk/dyrk1B is activated through Rac1-MKK3 signaling.
The serine/threonine kinase Mirk/dyrk1B is activated in several solid tumors where it mediates cell survival, but the mechanism by which Mirk is activated in tumors is unknown. We now demonstrate that Mirk is activated as a kinase by signaling from Rac1 to the mitogen-activated protein kinase kinase MKK3. Rac is a Ras superfamily GTPase that, when activated, functions downstream of Ras oncoproteins to promote cell survival, transformation, and membrane ruffling. The constitutively active mutant Rac1QL activated Mirk in several cell types through MKK3, which in turn activated Mirk by phosphorylation. Dominant negative Rac1, dominant negative MKK3, and knockdown of MKK3 by RNA interference inhibited the kinase activity of co-expressed Mirk. E-cadherin ligation in confluent Madin-Darby canine kidney (MDCK) epithelial cells is known to transiently activate Rac1. Mirk was activated by endogenous Rac1 following E-cadherin ligation in confluent MDCK epithelial cells, whereas treatment of confluent MDCK cells with an Rac1 inhibitor decreased Mirk activity. Disruption of cadherin ligation by EGTA or prevention of cadherin ligation by maintenance of cells at subconfluent density blocked activation of Mirk. Engagement of cadherin molecules on subconfluent cells by an E-cadherin/Fc chimeric molecule transiently activated both Rac1 and Mirk with a similar time course. Rac activity is up-regulated in many human tumors and mediates survival signals, which enable tumor cells to evade apoptosis. This study characterizes a new anti-apoptotic signaling pathway that connects Rac1 with a novel downstream effector, Mirk kinase, which has recently been demonstrated to mediate survival in human tumors.
Jin
Kideok
K
Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA.
Lim
Seunghwan
S
Mercer
Stephen E
SE
Friedman
Eileen
E
D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D004285:Dogs; D004789:Enzyme Activation; D006801:Humans; D048371:MAP Kinase Kinase 3 / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D015398:Signal Transduction; D014157:Transcription Factors; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D000097603:Dyrk Kinases
D048371:MAP Kinase Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D014157:Transcription Factors; D020830:rac1 GTP-Binding Protein; D000097603:Dyrk Kinases