Increased in vitro activation of EGFR by membrane-bound TGF-α from gastric and colonic mucosa of aged rats

Xiao, Zhi-Qiang, and Adhip P. N. Majumdar. Increased in vitro activation of EGFR by membrane-bound TGF-a from gastric and colonic mucosa of aged rats. Am J Physiol Gastrointest Liver Physiol 281: G111–G116, 2001.—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-a (TGF-a) may modulate EGFR function through an autocrine/juxtacrine mechanism. The present study aimed to determine the contribution of membrane-bound precursors of TGF-a 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 18to 20-kDa membrane-bound precursor forms of TGF-a. The amount of TGF-a 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-a from gastric and colonic mucosal membranes of aged rats caused a 200– 250% higher activation of EGFR and extracellular signalrelated kinases (p42/44) compared with young rats. Our data suggest that the membrane-bound precursor form(s) of TGF-a may partly be responsible for enhancing EGFR activation in the gastric and colonic mucosa of aged rats, probably though an autocrine/juxtacrine mechanism(s).