title: Insulin receptor substrate-4 is expressed in muscle tissue without acting as a substrate for the insulin receptor.
abstract: Insulin receptor substrate (IRS) proteins represent key elements of the insulin-signaling cascade. IRS-4 is the most recently characterized member of the IRS family with an undefined in vivo function. In contrast to IRS-1 and IRS-2, IRS-4 exhibits a limited tissue expression, and IRS-4 protein has not been detected in any mouse or primary human tissue so far. The purpose of the present study was to analyze the expression of IRS-4 in rat muscle and human skeletal muscle cells and assess involvement of IRS-4 in initial insulin signaling. Using immunoblotting and immunoprecipitation, the specific expression of IRS-4 protein could be demonstrated in rat soleus and cardiac muscle and human skeletal muscle cells, but it was not significantly detectable in quadriceps and gastrocnemius. A prominent down-regulation of IRS-4 was observed in heart and soleus muscle of WOKW rats, an animal model of the metabolic syndrome. In human skeletal muscle cells, both IRS-1 and IRS-2 are rapidly phosphorylated on tyrosine in response to insulin, whereas essentially no tyrosine phosphorylation of IRS-4 was observed in response to both insulin and IGF-I. Instead, a 2-fold increase in IRS-4 tyrosine phosphorylation was observed in myocytes subjected to osmotic stress. In conclusion, IRS-4 protein is expressed in heart and skeletal muscle in a fiber type specific fashion. Our data suggest that IRS-4 does not function as a substrate of the insulin and the IGF-I receptor in primary muscle cells but may be involved in nonreceptor tyrosine kinase signaling.
authors.affiliation: Molecular Cardiology, Department of Clinical Biochemistry and Pathobiochemistry, German Diabetes Research Institute, D-40225 Düsseldorf, Germany. eckel@uni-duesseldorf.de
authors.forename: Sylvia
authors.initials: S
authors.lastname: Schreyer
authors.forename: Daniela
authors.initials: D
authors.lastname: Ledwig
authors.forename: Irini
authors.initials: I
authors.lastname: Rakatzi
authors.forename: Ingrid
authors.initials: I
authors.lastname: Klöting
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eckel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007004:Hypoglycemic Agents; C107686:IRS4 protein, human; C491532:IRS4 protein, rat; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C491531:Irs4 protein, mouse; D010750:Phosphoproteins; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin