THE DROSOPHILA INSULIN-RECEPTOR HOMOLOG - A GENE ESSENTIAL FOR EMBRYONIC-DEVELOPMENT ENCODES 2 RECEPTOR ISOFORMS WITH DIFFERENT SIGNALING POTENTIAL

We report the cloning and primary structure of the Drosophila insulin receptor gene (inr), functional expression of the predicted polypeptid e, and the isolation of mutations in the inr locus, Our data indicate that the structure and processing of the Drosophila insulin prorecepto r are somewhat different from those of the mammalian insulin and IGF 1 receptor precursors. The INR proreceptor (M(r) 280 kDa) is processed proteolytically to generate an insulin-binding alpha subunit (M(r) 120 kDa) and a beta subunit (M(r) 170 kDa) with protein tyrosine kinase d omain, The INR beta(170) subunit contains a novel domain at the carbox yterminal side of the tyrosine kinase, in the form of a 60 kDa extensi on which contains multiple potential tyrosine autophosphorylation site s, This 60 kDa G-terminal domain undergoes cell-specific proteolytic c leavage which leads to the generation of a total of four polypeptides (alpha(120), beta(170), beta(90) and a free 60 kDa C-terminus) from th e inr gene. These subunits assemble into mature INR receptors with the structures alpha(2)(beta(170))(2) or alpha(2)(beta(90))(2). Mammalian insulin stimulates tyrosine phosphorylation of both types of beta sub units, which in turn allows the beta(170), but not the beta(90) subuni t, to bind directly to p85 SH2 domains of PI-3 kinase, It is likely th at the two different isoforms of INR have different signaling potentia ls, Finally, we show that loss of function mutations in the inr gene, induced by either a P-element insertion occurring within the predicted ORF, or by ethylmethane sulfonate treatment, render pleiotropic reces sive phenotypes that lead to embryonic lethality, The activity of inr appears to be required in the embryonic epidermis and nervous system a mong others, since development of the cuticle, as well as the peripher al and central nervous systems are affected by inr mutations.