RIP2 is a Raf1-activated mitogen-activated protein kinase kinase.
RIP2 is a serine-threonine kinase associated with the tumor necrosis factor (TNF) receptor complex and is implicated in the activation of NF-kappaB and cell death in mammalian cells. However, the function of its kinase domain is still enigmatic as it is not required in engaging these responses. Here we show that RIP2 activates the extracellular signal-regulated kinase (ERK) pathway and that the kinase activity of RIP2 appears to be important in this process. RIP2 activates AP-1 and serum response element regulated expression by inducing the activation of the Elk1 transcription factor. RIP2 directly phosphorylates and activates ERK2 in vivo and in vitro. RIP2 in turn is activated through its interaction with Ras-activated Raf1. Kinase-defective point and deletion variants of RIP2 also significantly blocked the activation of ERK2 by TNFalpha but not epidermal growth factor. These results describe a novel pathway of ERK activation and the first catalytic function ascribed to any of the RIP-like kinases associated with the TNF receptor superfamily.
Navas
T A
TA
Department of Endocrine Research, Genentech, Inc., South San Francisco, California 94080, USA.
Baldwin
D T
DT
Stewart
T A
TA
D000818:Animals; D019556:COS Cells; D002384:Catalysis; D002460:Cell Line; D004789:Enzyme Activation; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism
D018124:Receptors, Tumor Necrosis Factor; D006160:Guanosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases