Kinase suppressor of Ras is ceramide-activated protein kinase

Cell. 1997 Apr 4;89(1):63-72. doi: 10.1016/s0092-8674(00)80183-x.

Abstract

A proline-directed serine/threonine ceramide-activated protein (CAP) kinase mediates transmembrane signaling through the sphingomyelin pathway. CAP kinase reportedly initiates proinflammatory TNF alpha action by phosphorylating and activating Raf-1. The present studies delineate kinase suppressor of Ras (KSR), identified genetically in Caenorhabditis elegans and Drosophila, as CAP kinase. Mouse KSR, like CAP kinase, renatures and autophosphorylates as a 100-kDa membrane-bound polypeptide. KSR overexpression constitutively activates Raf-1. TNF alpha or ceramide analogs markedly enhance KSR autophosphorylation and its ability to complex with, phosphorylate, and activate Raf-1. In vitro, low nanomolar concentrations of natural ceramide stimulate KSR to autophosphorylate, and transactivate Raf-1. Other lipid second messengers were ineffective. Moreover, Thr269 the Raf-1 site phosphorylated by CAP kinase, is also recognized by KSR. Thus, by previously established criteria, KSR appears to be CAP kinase.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells / enzymology
  • Caenorhabditis elegans
  • Ceramides / pharmacology
  • Drosophila
  • Gene Expression Regulation, Enzymologic / physiology
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutagenesis / physiology
  • Phosphorylation
  • Protein Kinases / drug effects
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / pharmacology*
  • Proto-Oncogene Proteins c-raf
  • Signal Transduction / physiology*
  • Threonine / genetics
  • Tumor Necrosis Factor-alpha / pharmacology
  • ras Proteins / antagonists & inhibitors*

Substances

  • Ceramides
  • Tumor Necrosis Factor-alpha
  • Threonine
  • Protein Kinases
  • KSR-1 protein kinase
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • ras Proteins