Src supports UDP-glucuronosyltransferase-2B7 detoxification of catechol estrogens associated with breast cancer.
Mammary gland-distributed and ER-bound UDP-glucuronosyltransferase (UGT)-2B7 metabolizes genotoxic catechol-estrogens (CE) associated with breast cancer initiation. Although UGT2B7 has 3 PKC- and 2 tyrosine kinase (TK)-sites, its inhibition by genistein, herbimycin-A and PP2 with parallel losses in phospho-tyrosine and phospho-Y438-2B7 content indicated it requires tyrosine phosphorylation, unlike required PKC phosphorylation of UGT1A isozymes. 2B7 mutants at PKC-sites had essentially normal activity, while its TK-sites mutants, Y236F- and Y438F-2B7, were essentially inactive. Overexpression of regular or active Src, but not dominant-negative Src, in 2B7-transfected COS-1 cells increased 2B7 activity and phospho-Y438-2B7 by 50%. Co-localization of 2B7 and regular SrcTK in COS-1 cells that was dissociated by pretreatment with Src-specific PP2-inhibitor provided strong evidence Src supports 2B7 activity. Consistent with these findings, evidence indicates an appropriate set of ER proteins with Src-homology binding-domains, including 2B7 and well-known multi-functional Src-engaged AKAP12 scaffold, supports Src-dependent phosphorylation of CE-metabolizing 2B7 enabling it to function as a tumor suppressor.
Mitra
Partha S
PS
Section on Genetic Disorders of Drug Metabolism, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892-1830, USA.
Basu
Nikhil K
NK
Owens
Ida S
IS
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004249:DNA Damage; D002393:Estrogens, Catechol / Q000378:metabolism*; D019833:Genistein / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives; D014162:Transfection; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
C412373:AG 1879; D016227:Benzoquinones; D002393:Estrogens, Catechol; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011960:Receptors, Estrogen; D017828:Rifabutin; C020754:herbimycin; D019833:Genistein; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D019061:src-Family Kinases; D011493:Protein Kinase C