NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain

EMBO J. 1997 Mar 17;16(6):1279-90. doi: 10.1093/emboj/16.6.1279.

Abstract

Nck, an adaptor protein composed of one SH2 and three SH3 domains, is a common target for a variety of cell surface receptors. We have identified a novel mammalian serine/threonine kinase that interacts with the SH3 domains of Nck, termed Nck Interacting Kinase (NIK). This kinase is most homologous to the Sterile 20 (Ste20) family of protein kinases. Of the members of this family, GCK and MSST1 are most similar to NIK in that they bind neither Cdc42 nor Rac and contain an N-terminal kinase domain with a putative C-terminal regulatory domain. Transient overexpression of NIK specifically activates the stress-activated protein kinase (SAPK) pathway. Both the kinase domain and C-terminal regulatory region of NIK are required for full activation of SAPK. NIK likely functions upstream of MEKK1 to activate this pathway; a dominant-negative MEK kinase 1 (MEKK1) blocks activation of SAPK by NIK. MEKK1 and NIK also associate in cells and this interaction is mediated by regulatory domains on both proteins. Two other members of this kinase family, GCK and HPK1, contain C-terminal regulatory domains with homology to that of NIK. These findings indicate that the C-terminal domain of these proteins encodes a new protein domain family and suggests that this domain couples these kinases to the SAPK pathway, possibly by interacting with MEKK1 or related kinases.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line
  • Cloning, Molecular
  • Conserved Sequence
  • DNA, Complementary / genetics
  • Enzyme Activation
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • Mitogen-Activated Protein Kinase Kinases*
  • Mitogen-Activated Protein Kinases*
  • Molecular Sequence Data
  • Molecular Weight
  • Oncogene Proteins / metabolism*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins*
  • Sequence Homology, Amino Acid
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA, Complementary
  • Intracellular Signaling Peptides and Proteins
  • Nck protein
  • Oncogene Proteins
  • Saccharomyces cerevisiae Proteins
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • NF-kappa B kinase
  • STE20 protein, S cerevisiae
  • Mitogen-Activated Protein Kinase Kinases

Associated data

  • GENBANK/U88984