COT is an oncogene that can activate both the MAP kinase and JNK kinase pathways. COT activates I?B kinases and induces the nuclear production of NF-?B. C-terminal catalytic domain of KSR2 associates with COT and KSR2 can negatively regulates the kinase activity of COT in vitro. Co-transfection of KSR2 with COT in cells lead to reduced COT-mediated ERK activation and COT-induced IL8 production in a dose-dependent manner. COT is one of the MAP kinase kinase kinases that regulates the ERK1/ERK2 pathway in response to IL-1. Blockage of expression of COT results in failure of IL-1 to induce an increase in IL-8 and MIP-1betamRNA levels.

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