The proto-oncogene Cot kinase participates in CD3/CD28 induction of NF-kappaB acting through the NF-kappaB-inducing kinase and IkappaB kinases

Immunity. 1999 Feb;10(2):271-80. doi: 10.1016/s1074-7613(00)80027-8.

Abstract

The proto-oncogene Cot/Tpl-2 encodes a MAP3K-related serine-threonine kinase. Expression of wild type Cot activates the IkappaB kinases (IKK) leading to induction of NF-kappaB. Conversely, expression of kinase-deficient Cot inhibits CD3/CD28 but not TNF alpha induction of NF-kappaB. 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-kappaB. In contrast, a kinase-deficient mutant of the NF-kappaB-inducing kinase (NIK) inhibits both CD3/CD28 and TNF alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CD28 Antigens / metabolism*
  • CD3 Complex / metabolism*
  • Enzyme Induction
  • Humans
  • I-kappa B Kinase
  • Jurkat Cells
  • MAP Kinase Kinase Kinases*
  • NF-kappa B / isolation & purification*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic

Substances

  • CD28 Antigens
  • CD3 Complex
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Transcription Factor AP-1
  • Protein-Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • MAP Kinase Kinase Kinases
  • MAP3K8 protein, human
  • NF-kappa B kinase