The PAG gene product, a stress-induced protein with antioxidant properties, is an Abl SH3-binding protein and a physiological inhibitor of c-Abl tyrosine kinase activity

Genes Dev. 1997 Oct 1;11(19):2456-67. doi: 10.1101/gad.11.19.2456.

Abstract

Biochemical and genetic evidence suggests that the tyrosine kinase activity of c-Abl is tightly regulated in vivo by a cellular factor binding to the Src homology 3 (SH3) domain of Abl. We used the yeast two-hybrid system to identify a gene, PAG, whose protein product (Pag) interacts specifically with the Abl SH3 domain. Pag, also known as macrophage 23-kD stress protein (MSP23), is a member of a novel family of proteins with antioxidant activity implicated in the cellular response to oxidative stress and in control of cell proliferation and differentiation. In a co-expression assay, Pag associates with c-Abl in vivo and inhibits tyrosine phosphorylation induced by overexpression of c-Abl. Inhibition requires the Abl SH3 and kinase domains and is not observed with other Abl SH3-binding proteins. Expression of Pag also inhibits the in vitro kinase activity of c-Abl, but not SH3-mutated Abl or v-Abl. When transfected in NIH-3T3 cells, Pag is localized to nucleus and cytoplasm and rescues the cytostatic effect induced by c-Abl. These observations suggest Pag is a physiological inhibitor of c-Abl in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antioxidants / metabolism
  • Cell Line
  • Cell Nucleus / chemistry
  • Cloning, Molecular
  • Cytoplasm / chemistry
  • Gene Expression Regulation
  • Heat-Shock Proteins / analysis
  • Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins / pharmacology
  • Humans
  • Mice
  • Molecular Sequence Data
  • Oncogene Proteins v-abl / metabolism
  • Oxidative Stress
  • Peroxidases*
  • Peroxiredoxins
  • Phosphotyrosine / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Sequence Analysis, DNA
  • Transfection
  • src Homology Domains*

Substances

  • Antioxidants
  • Heat-Shock Proteins
  • Oncogene Proteins v-abl
  • Phosphotyrosine
  • Peroxidases
  • PRDX1 protein, human
  • Peroxiredoxins
  • Prdx1 protein, mouse
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-abl