Transmembrane signaling byaninsulin receptor lacking a cytoplasmic ,8-subunit domain

Toassess thefunction ofthecytoplasmic domain oftheinsulin receptor (IR) 13subunit, wehavestudied amutant IRtruncated by365aa(HIRA978), thereby deleting >90%ofthecytoplasmic domain. H1RA978 receptors were processed normally tohomodimers that wereexpressed atthe cell surface wheretheybindinsulin withnormalaffinity. Although these truncated IRswereinactive withrespect to ligand-induced internalition andautophosphorylation, insu- linstimulated endogenous substrate (pp185) phosphorylation signiicantly moreinH1RA978 cells thaninuntransfected Ratl cells. Importantly, despite absence ofthe«-subunit cytoplas- micdomain, fibroblasts expressing EHIRA978 receptors dis- played enhanced sensitivity toinsulin forstimulation ofglucose incorporation intoglycogen, a-aminoisobutyric aciduptake, thymidine incorporation, andS6kinase activity compared with parental fibroblasts. Insulin also induced theexpression ofthe protooncogene c-fos andtheearly growth response geneEgr-l inHIRA978 cells fargreater thaninparental Ratlfibroblasts. Furthermore, anagonistic monoclonal antibody specific forthe humanIRstimulated insulin action infibroblasts expressing wild-type humanIRbuthadnoeffect onHIRA978 cells. In conclusion, theEIRA978truncated IRsappeartoconfer enhanced insulin sensitivity byaugmenting thesignaling prop- erties oftheendogenous rodent IRs. Theinsulin receptor (IR)isaheterotetrameric membrane