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PMID: 9334312 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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 & development ·Vol. 11 ·No. 19 ·1997-10-01 ·Pages 2456-67

Wen ST, Van Etten RA

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.

MeSH Terms
Amino Acid Sequence Animals Antioxidants/metabolism Cell Line Cell Nucleus/chemistry Cloning, Molecular Cytoplasm/chemistry Gene Expression Regulation Heat-Shock Proteins/analysis,metabolism,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,metabolism Sequence Analysis, DNA Transfection src Homology Domains
Chemicals
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
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Wen S T
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Van Etten R A
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.11.19.2456
Published
1997-10-01
Pages
2456-67
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC316562
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.11.19.2456 PMC Full Text View journal details
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