The differential effects of pp120 (Ceacam 1) on the mitogenic action of insulin and insulin-like growth factor 1 are regulated by the nonconserved tyrosine 1316 in the insulin receptor

pp120 (Ceacam 1) undergoes ligand-stimulated phosphorylation by the insulin receptor, but not by the insulin-like growth factor 1 receptor (IGF-1R). T his differential phosphorylation is regulated by the C terminus of the beta -subunit of the insulin receptor, the least conserved domain of the two rec eptors. In the present studies, deletion and site-directed mutagenesis in s tably transfected hepatocytes derived from insulin receptor knockout mice ( IR-/-) revealed that Tyr(1316), which is replaced by the nonphosphorylatabl e phenylalanine in IGP-1R, regulated the differential phosphorylation of pp 120 by the insulin receptor. Similarly, the nonconserved Tyr(1316) residue also regulated the differential effect of pp120 on IGF-1 and insulin mitoge nesis, with pp120 downregulating the growth-promoting action of insulin, bu t not that of IGF-1. Thus, it appears that pp120 phosphorylation by the ins ulin receptor is required and sufficient to mediate its downregulatory effe ct on the mitogenic action of insulin. Furthermore, the current studies rev ealed that the C terminus of the beta-subunit of the insulin receptor conta ins elements that suppress the mitogenic action of insulin. Because IR-/- h epatocytes are derived from liver, an insulin-targeted tissue, our observat ions have finally resolved the controversy about the role of the least-cons erved domain of insulin and IGF-1Rs in mediating the difference in the mito genic action of their ligands, with IGF-1 being more mitogenic than insulin .