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).