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.
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.
Wen
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Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Van Etten
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D000595:Amino Acid Sequence; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D003001:Cloning, Molecular; D003593:Cytoplasm / Q000737:chemistry; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016374:Oncogene Proteins v-abl / Q000378:metabolism; D018384:Oxidative Stress; D010544:Peroxidases; D054464:Peroxiredoxins; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D014162:Transfection; D018909:src Homology Domains
D000975:Antioxidants; D006360:Heat-Shock Proteins; D016374:Oncogene Proteins v-abl; D019000:Phosphotyrosine; D010544:Peroxidases; C515940:PRDX1 protein, human; D054464:Peroxiredoxins; C489899:Prdx1 protein, mouse; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl