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from gastric and colonic mucosa of aged
rats
2 Veterans Affairs Medical Center and 1 Departments of Internal Medicine and 3 Biochemistry and Molecular Biology and 4 Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201
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-
(TGF-) may modulate EGFR function through an
autocrine/juxtacrine mechanism. The present study aimed to determine
the contribution of membrane-bound precursors of TGF- 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-. The amount of TGF- 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- 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-
may partly be responsible for enhancing EGFR activation in the gastric
and colonic mucosa of aged rats, probably though an
autocrine/juxtacrine mechanism(s).
epidermal growth factor receptor signal transduction; tyrosine
kinase; autocrine/juxtacrine mechanism; transforming growth
factor-
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