The Proto-Oncogene Cot Kinase Participates in CD3/CD28 Induction of NF-κB Acting through the NF-κB-Inducing Kinase and IκB Kinases

The proto-oncogene Cot/Tpl-2 encodes a MAP3K-related serine-threonine kinase. Expression of wild type Cot activates the IκB kinases (IKK) leading to induction of NF-κB. Conversely, expression of kinase-deficient Cot inhibits CD3/CD28 but not TNFα induction of NF-κB. These findings suggest the selective involvement of Cot/Tpl-2 or a closely related kinase in the CD3/CD28 costimulatory pathway leading to induced nuclear expression of NF-κB. In contrast, a kinase-deficient mutant of the NF-κB-inducing kinase (NIK) inhibits both CD3/CD28 and TNFα signaling, indicating that these pathways converge at or prior to the action of NIK. Consistent with such a sequential function of these two kinases, Cot physically assembles with and phosphorylates NIK in vivo.