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