Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway

Curr Biol. 1996 May 1;6(5):598-605. doi: 10.1016/s0960-9822(02)00546-8.

Abstract

Background: The Rho-related GTP-binding proteins Cdc42 and Rac1 have been shown to regulate signaling pathways involved in cytoskeletal reorganization and stress-responsive JNK (Jun N-terminal kinase) activation. However, to date, the GTPase targets that mediate these effects have not been identified. PAK defines a growing family of mammalian kinases that are related to yeast Ste20 and are activated in vitro through binding to Cdc42 and Rac1 (PAK: p21 Cdc42-/Rac-activated kinase). Clues to PAK function have come from studies of Ste20, which controls the activity of the yeast mating mitogen-activated protein (MAP) kinase cascade, in response to a heterotrimeric G protein and Cdc42.

Results: To initiate studies of mammalian Ste20-related kinases, we identified a novel human PAK isoform, hPAK1. When expressed in yeast, hPAK1 was able to replace Ste20 in the pheromone response pathway. Chemical mutagenesis of a plasmid encoding hPAK1, followed by transformation into yeast, led to the identification of a potent constitutively active hPAK1 with a substitution of a highly conserved amino-acid residue (L107F) in the Cdc42-binding domain. Expression of the hPAK1(L107F) allele in mammalian cells led to specific activation of the Jun N-terminal kinase MAP kinase pathway, but not the mechanistically related extracellular signal-regulated MAP kinase pathway.

Conclusions: These results demonstrate that hPAK1 is a GTPase effector controlling a downstream MAP kinase pathway in mammalian cells, as Ste20 does in yeast. Thus, PAK and Ste20 kinases play key parts in linking extracellular signals from membrane components, such as receptor-associated G proteins and Rho-related GTPases, to nuclear responses, such as transcriptional activation.

Publication types

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

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • Base Sequence
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cloning, Molecular
  • DNA, Complementary
  • Enzyme Activation
  • GTP Phosphohydrolases / metabolism*
  • GTP-Binding Proteins / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases*
  • Molecular Sequence Data
  • Mutagenesis
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins*
  • Signal Transduction
  • cdc42 GTP-Binding Protein
  • p21-Activated Kinases

Substances

  • Cell Cycle Proteins
  • DNA, Complementary
  • Saccharomyces cerevisiae Proteins
  • PRK1 protein, S cerevisiae
  • PAK1 protein, human
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • cdc42 GTP-Binding Protein

Associated data

  • GENBANK/U51120