title: Increased in vitro activation of EGFR by membrane-bound TGF-alpha from gastric and colonic mucosa of aged rats.
abstract: Although aging is associated with increased epidermal growth factor receptor (EGFR) tyrosine kinase activity in Fischer 344 rat gastric and colonic mucosa, the regulatory mechanisms for the age-related rise in EGFR tyrosine kinase are poorly understood. Transmembrane transforming growth factor-alpha (TGF-alpha) may modulate EGFR function through an autocrine/juxtacrine mechanism. The present study aimed to determine the contribution of membrane-bound precursors of TGF-alpha in enhancing EGFR activation in the gastric and colonic mucosa during aging. The extent of EGFR tyrosine phosphorylation, a measure of EGFR activation, was substantially higher (300--350%) in the gastric and colonic mucosa of 23- (aged) vs. 4-mo-old (young) Fischer 344 rats. This was accompanied by an increase (200--1,000%) in the relative concentration of 18- to 20-kDa membrane-bound precursor forms of TGF-alpha. The amount of TGF-alpha bound to EGFR was also higher (150-250%) in the gastric and colonic mucosa of aged vs. young rats. In vitro studies revealed that exposure of HCT 116 cells (a colon cancer cell line) to TGF-alpha from gastric and colonic mucosal membranes of aged rats caused a 200--250% higher activation of EGFR and extracellular signal-related kinases (p42/44) compared with young rats. Our data suggest that the membrane-bound precursor form(s) of TGF-alpha may partly be responsible for enhancing EGFR activation in the gastric and colonic mucosa of aged rats, probably though an autocrine/juxtacrine mechanism(s).
authors.affiliation: Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Xiao
authors.forename: A P
authors.initials: AP
authors.lastname: Majumdar
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology; D003106:Colon / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism*; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
chemical_list: D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases