CDNA CLONING OF THE RAT IGF-I RECEPTOR - STRUCTURAL-ANALYSIS OF RAT AND HUMAN IGF-I AND INSULIN-RECEPTORS REVEALS DIFFERENCES IN ALTERNATIVE SPLICING AND RECEPTOR-SPECIFIC DOMAIN CONSERVATION

IGF I and insulin receptors are homologous proteins that function in d istinct physiological pathways. To define domains that might contribut e to differences between IGF I and insulin receptors, we cloned the ra t IGF I receptor cDNA and performed a comparative sequence analysis of specific functional domains in the two receptor types of rats and hum ans. Since alternative splicing has been shown to alter the activities of both IGF I and insulin receptors, we also examined the mRNA splici ng patterns of the two receptors. The C-terminal region exhibits the l owest degree of amino acid homology between rat and human IGF I recept ors (85%) and the tyrosine kinase domain the highest homology (98%). I n the region corresponding to the CAG+/- alternative splicing site of the human IGF I receptor, a nucleotide change in the rat eliminates th e alternative acceptor splice site. The rat IGF I receptor has no equi valent to the alternatively spliced exon 11 of the insulin receptor. T he IGF I and insulin receptors are highly homologous in the tyrosine k inase domain (84%), but differ markedly in other specific regions (e.g ., 22-26% homology in the transmembrane domain, 45% homology in the C- terminal domain). We speculate that these regions of divergent sequenc e may have roles in determining distinct signaling properties of IGF I and insulin receptors. (C) 1994 Academic Press, Inc.