Aging and gastrointestinal malignancies, including that of the stomach are associated with increased activation of EGF-receptor (EGFR). Although the intracellular events that regulate this process are poorly understood, we hypothesize that loss of ERRP (EGFR-related protein; GenBank accession number AF187818), a recently identified negative regulator of EGFR, that possesses a substantial homology to the ligand binding extracellular domain of EGFR, may contribute to this event. In support of our hypothesis, we have observed that in Fischer-344 rats, whereas aging is associated with increased activation of EGFR in the gastric mucosa, expression of ERRP decreases inthis tissue during this period. The latter is accompanied by a concomitant reduction in the amount of TGF-alpha bound to ERRP. In contrast, the amount of TGF-alpha bound to EGFR is found to be higher in the gastric mucosa of aged than in young rats. This is accompanied by a concomitant rise in EGFR levels. In the gastric mucosa, EGFR and ERRP are found to be colocalized. Gastric adenocarcinoma in humans, which has been shown to be associated with increased activation of EGFR, shows a substantial reduction in ERRP expression, when compared with benign tissues. We conclude that increased activation of EGFR in the gastric mucosa during aging and carcinogenesis may partly be due to the loss of ERRP.