PMID- 23478262 OWN - NLM STAT- MEDLINE DCOM- 20130617 LR - 20211021 IS - 1098-5549 (Electronic) IS - 0270-7306 (Print) IS - 0270-7306 (Linking) VI - 33 IP - 10 DP - 2013 May TI - The AP-1 complex regulates intracellular localization of insulin receptor substrate 1, which is required for insulin-like growth factor I-dependent cell proliferation. PG - 1991-2003 LID - 10.1128/MCB.01394-12 [doi] AB - The activation of the insulin/insulin-like growth factor I (IGF-I) receptor and the subsequent tyrosine phosphorylation of insulin receptor substrates (IRSs) are key initial events in a variety of insulin/IGF bioactivities, including mitogenesis. It has been reported that IRS-1 associates with intracellular membrane compartments, and this localization is believed to be important for insulin/IGF signal transduction. However, the molecular mechanisms underlying IRS-1 localization remain unclear. Here we show that in L6 myoblasts, IRS-1 associates with mu1A of the ubiquitously expressed AP-1 complex, which packages cargo proteins into clathrin-coated vesicles derived from intracellular membranes. While wild-type IRS-1 was predominantly localized to vesicular structures, IRS-1 mutants lacking three YXXPhi motifs responsible for binding to mu1A were mislocalized to the mannose-6-phosphate receptor-positive structures, suggesting that AP-1-dependent transport to peripheral vesicles is inhibited in these mutants. Furthermore, deletion of AP-1 binding sites in IRS-1 impaired IGF-I-induced cell proliferation, accompanied by reduced tyrosine phosphorylation of IRS-1 and its association with phosphoinositide (PI) 3-kinase. These data demonstrate the importance of AP-1-dependent localization of IRS-1 in mediating IGF-I-stimulated signaling and maximum mitogenic response. FAU - Yoneyama, Yosuke AU - Yoneyama Y AD - Department of Animal Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. FAU - Matsuo, Masao AU - Matsuo M FAU - Take, Kazumi AU - Take K FAU - Kabuta, Tomohiro AU - Kabuta T FAU - Chida, Kazuhiro AU - Chida K FAU - Hakuno, Fumihiko AU - Hakuno F FAU - Takahashi, Shin-Ichiro AU - Takahashi S LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130311 PL - United States TA - Mol Cell Biol JT - Molecular and cellular biology JID - 8109087 RN - 0 (AP1M1 protein, human) RN - 0 (Adaptor Protein Complex 1) RN - 0 (Adaptor Protein Complex mu Subunits) RN - 0 (IRS1 protein, human) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Protein Subunits) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) SB - IM MH - Adaptor Protein Complex 1/*metabolism MH - Adaptor Protein Complex mu Subunits/*metabolism MH - Amino Acid Sequence MH - Animals MH - Binding Sites MH - Cell Membrane/metabolism MH - *Cell Proliferation MH - DNA Replication MH - Gene Knockdown Techniques MH - HEK293 Cells MH - Humans MH - Insulin Receptor Substrate Proteins/chemistry/*metabolism MH - Insulin-Like Growth Factor I/*physiology MH - Molecular Sequence Data MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphorylation MH - Protein Binding MH - Protein Interaction Domains and Motifs MH - Protein Processing, Post-Translational MH - Protein Subunits MH - Protein Transport MH - Rats MH - Time-Lapse Imaging PMC - PMC3647963 EDAT- 2013/03/13 06:00 MHDA- 2013/06/19 06:00 PMCR- 2013/11/01 CRDT- 2013/03/13 06:00 PHST- 2013/03/13 06:00 [entrez] PHST- 2013/03/13 06:00 [pubmed] PHST- 2013/06/19 06:00 [medline] PHST- 2013/11/01 00:00 [pmc-release] AID - MCB.01394-12 [pii] AID - 01394-12 [pii] AID - 10.1128/MCB.01394-12 [doi] PST - ppublish SO - Mol Cell Biol. 2013 May;33(10):1991-2003. doi: 10.1128/MCB.01394-12. Epub 2013 Mar 11.