Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade

Genes Dev. 1996 Sep 15;10(18):2251-64. doi: 10.1101/gad.10.18.2251.

Abstract

The c-Jun amino-terminal kinases (JNKs)/stress-activated protein kinases (SAPKs) play a crucial role in stress responses in mammalian cells. The mechanism underlying this pathway in the hematopoietic system is unclear, but it is a key in understanding the molecular basis of blood cell differentiation. We have cloned a novel protein kinase, termed hematopoietic progenitor kinase 1 (HPK1), that is expressed predominantly in hematopoietic cells, including early progenitor cells. HPK1 is related distantly to the p21(Cdc42/Rac1)-activated kinase (PAK) and yeast STE20 implicated in the mitogen-activated protein kinase (MAPK) cascade. Expression of HPK1 activates JNK1 specifically, and it elevates strongly AP-1-mediated transcriptional activity in vivo. HPK1 binds and phosphorylates MEKK1 directly, whereas JNK1 activation by HPK1 is inhibited by a dominant-negative MEKK1 or MKK4/SEK mutant. Interestingly, unlike PAK65, HPK1 does not contain the small GTPase Rac1/Cdc42-binding domain and does not bind to either Rac1 or Cdc42, suggesting that HPK1. activation is Rac1/Cdc42-independent. These results indicate that HPK1 is a novel functional activator of the JNK/SAPK signaling pathway.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cloning, Molecular
  • Enzyme Activation
  • GTP-Binding Proteins / metabolism
  • Hematopoietic Stem Cells / enzymology*
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4*
  • MAP Kinase Kinase Kinase 1*
  • Mitogen-Activated Protein Kinase Kinases*
  • Mitogen-Activated Protein Kinases*
  • Molecular Sequence Data
  • Mutation
  • Phosphorylation
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • RNA, Messenger / biosynthesis
  • Signal Transduction
  • Tissue Distribution
  • Transcription Factor AP-1 / metabolism
  • cdc42 GTP-Binding Protein
  • rac GTP-Binding Proteins

Substances

  • Cell Cycle Proteins
  • RNA, Messenger
  • Transcription Factor AP-1
  • Protein Kinases
  • hematopoietic progenitor kinase 1
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • GTP-Binding Proteins
  • cdc42 GTP-Binding Protein
  • rac GTP-Binding Proteins

Associated data

  • GENBANK/U66464