title: Insulin receptor substrates form high-molecular-mass complexes that modulate their availability to insulin/insulin-like growth factor-I receptor tyrosine kinases.
abstract: Insulin receptor substrates (IRSs) are phosphorylated by activated insulin/insulin-like growth factor (IGF)-I receptor tyrosine kinases. Phosphotyrosyl IRSs are recognized by signaling molecules possessing src homology region 2 (SH2) domains, which mediate various insulin/IGF bioactivities. However, we have shown that IRSs are also associated with other proteins by a phosphotyrosine-independent mechanism. Here, we demonstrated that IRSs form high-molecular-mass complexes (we named these complexes IRSomes) with various proteins and we elucidated their possible roles. Blue native-polyacrylamide gel electrophoresis of cell lysates revealed IRSome formation. Some proteins associated with IRSs in IRS-isoform-, cell-type-, or stimulus-specific manners. Results of the in vitro tyrosine phosphorylation assay indicated that tyrosine phosphorylation of IRS-1 by insulin receptor was decreased when IRS-1 was contained in IRSomes prepared from 3T3-L1 adipocytes treated with TNF-α. Also, tyrosine phosphorylation of IRS-2 by IGF-I receptor was increased when IRS-2 was contained in IRSomes prepared from FRTL-5 thyrocytes treated with dibutyryl cAMP. These results demonstrated that cytokine/hormone-induced formation of IRSomes modulates availability of IRSs to receptor tyrosine kinases.
authors.affiliation: Department of Animal Sciences, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukushima
authors.forename: Toshiya
authors.initials: T
authors.lastname: Arai
authors.forename: Miyako
authors.initials: M
authors.lastname: Ariga-Nedachi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okajima
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ooi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Iijima
authors.forename: Meri
authors.initials: M
authors.lastname: Sone
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Cho
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Ando
authors.forename: Kohei
authors.initials: K
authors.lastname: Kasahara
authors.forename: Atsufumi
authors.initials: A
authors.lastname: Ozoe
authors.forename: Hidehito
authors.initials: H
authors.lastname: Yoshihara
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Chida
authors.forename: Shigeru
authors.initials: S
authors.lastname: Okada
authors.forename: John J
authors.initials: JJ
authors.lastname: Kopchick
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hakuno
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Takahashi
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D003994:Bucladesine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D046912:Multiprotein Complexes; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D003994:Bucladesine; D017526:Receptor, IGF Type 1