RIP2 is a Raf1-activated mitogen-activated protein kinase kinase

RIPS is a serine-threonine kinase associated with the tumor necrosis factor (TNF) receptor complex and is implicated in the activation of NF-kappa B 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 RIPE activates the extracellular signal-regulated kinase (ERR) pathway and that the kinase activity of RIPS appears to be important in this process. RIPS activates AP-1 and serum response element regulated expression by inducing the activation of the Elk1 transcription factor. RIPS 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 TNF alpha 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.