Recent observations suggest that transforming growth factor alpha (TGF-alpha), which binds to the epidermal growth factor (EGF) receptor (EGFR), may induce neoplastic growth of the colonic mucosa through an autocrine mechanism. To assess the functional role of TGF-alpha in colonic carcinogenesis the present investigation examines the changes in TGF-alpha-and EGF-induced activation of intrinsic tyrosine kinase (Tyr-k) activity of EGFR in the colonic mucosa of rats after administration of the colonic carcinogen azoxymethane (AOM; 20 mg/kg body wt). Five days after a single injection of AOM to 4- to 5-month old rats proliferative activity (as assessed by 5-bromo-2'-deoxyuridine immunoreactivity) in the colonic mucosa was increased by approximately 700% over the corresponding saline-injected controls. This was accompanied by: (i) a marked rise in autophosphorylation of a number of mucosal proteins, including one with a M(r) of 170 kDa, a molecular mass that corresponds to EGFR; (ii) a 110-130% increase in basal EGFR Tyr-k activity. Despite this rise in basal EGFR Tyr-k activity, exposure of isolated colonocytes or detergent-solubilized colonic mucosa from AOM-treated animals to either 1 x 10(-8) M TGF-alpha or EGF caused a further 90-160% increase in EGFR Tyr-k activity over the corresponding basal levels. In contrast, bombesin produced no apparent change in EGFR Tyr-k activity. We conclude that increased ligand-induced activation of EGFR Tyr-k may be an important event for development of the hyperproliferative state associated with induction of colorectal neoplasia.