| Structural highlights
Disease
[IRS1_HUMAN] Polymorphisms in IRS1 may be involved in the etiology of non-insulin-dependent diabetes mellitus (NIDDM) [MIM:125853].[1] [2] [3] [4] [5]
Function
[AP2M1_HUMAN] Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. The AP-2 mu subunit binds to transmembrane cargo proteins; it recognizes the Y-X-X-Phi motifs. The surface region interacting with to the Y-X-X-Phi motif is inaccessible in cytosolic AP-2, but becomes accessible through a conformational change following phosphorylation of AP-2 mu subunit at 'Tyr-156' in membrane-associated AP-2. The membrane-specific phosphorylation event appears to involve assembled clathrin which activates the AP-2 mu kinase AAK1 (By similarity). Plays a role in endocytosis of frizzled family members upon Wnt signaling (By similarity).[6] [7] [8] [9] [10] [11] [12] [IRS1_HUMAN] May mediate the control of various cellular processes by insulin. When phosphorylated by the insulin receptor binds specifically to various cellular proteins containing SH2 domains such as phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit (By similarity).[13] [14]
Publication Abstract from PubMed
Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways. Dysregulation of insulin signaling is linked to diabetes and cancer. The spindle checkpoint controls the fidelity of chromosome segregation during mitosis. Here, we show that insulin receptor substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote insulin receptor (IR) endocytosis through recruiting the clathrin adaptor complex AP2 to IR. A phosphorylation switch of IRS1/2 orchestrated by extracellular signal-regulated kinase 1 and 2 (ERK1/2) and Src homology phosphatase 2 (SHP2) ensures selective internalization of activated IR. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice. We propose that mitotic regulators and SHP2 promote feedback inhibition of IR, thereby limiting the duration of insulin signaling. Targeting this feedback inhibition can improve insulin sensitivity.
Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling.,Choi E, Kikuchi S, Gao H, Brodzik K, Nassour I, Yopp A, Singal AG, Zhu H, Yu H Nat Commun. 2019 Apr 1;10(1):1473. doi: 10.1038/s41467-019-09318-3. PMID:30931927[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Federici M, Pandolfi A, De Filippis EA, Pellegrini G, Menghini R, Lauro D, Cardellini M, Romano M, Sesti G, Lauro R, Consoli A. G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation. 2004 Jan 27;109(3):399-405. Epub 2004 Jan 5. PMID:14707024 doi:10.1161/01.CIR.0000109498.77895.6F
- ↑ Esposito DL, Mammarella S, Ranieri A, Della Loggia F, Capani F, Consoli A, Mariani-Costantini R, Caramia FG, Cama A, Battista P. Deletion of Gly723 in the insulin receptor substrate-1 of a patient with noninsulin-dependent diabetes mellitus. Hum Mutat. 1996;7(4):364-6. PMID:8723689 doi:<364::AID-HUMU13>3.0.CO;2-0 10.1002/(SICI)1098-1004(1996)7:4<364::AID-HUMU13>3.0.CO;2-0
- ↑ Mammarella S, Creati B, Esposito DL, Arcuri P, Della Loggia F, Capani F, Mariani-Costantini R, Caramia FG, Battista P, Cama A. Novel allele of the insulin receptor substrate-1 bearing two non-conservative amino acid substitutions in a patient with noninsulin-dependent diabetes mellitus. Mutations in brief no. 130. Online. Hum Mutat. 1998;11(5):411. PMID:10206679 doi:<411::AID-HUMU11>3.0.CO;2-2 10.1002/(SICI)1098-1004(1998)11:5<411::AID-HUMU11>3.0.CO;2-2
- ↑ Marini MA, Frontoni S, Mineo D, Bracaglia D, Cardellini M, De Nicolais P, Baroni A, D'Alfonso R, Perna M, Lauro D, Federici M, Gambardella S, Lauro R, Sesti G. The Arg972 variant in insulin receptor substrate-1 is associated with an atherogenic profile in offspring of type 2 diabetic patients. J Clin Endocrinol Metab. 2003 Jul;88(7):3368-71. PMID:12843189
- ↑ McGettrick AJ, Feener EP, Kahn CR. Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes IRS-1 to associate with the insulin receptor and inhibit receptor autophosphorylation. J Biol Chem. 2005 Feb 25;280(8):6441-6. Epub 2004 Dec 7. PMID:15590636 doi:10.1074/jbc.M412300200
- ↑ Fraile-Ramos A, Kohout TA, Waldhoer M, Marsh M. Endocytosis of the viral chemokine receptor US28 does not require beta-arrestins but is dependent on the clathrin-mediated pathway. Traffic. 2003 Apr;4(4):243-53. PMID:12694563
- ↑ Motley A, Bright NA, Seaman MN, Robinson MS. Clathrin-mediated endocytosis in AP-2-depleted cells. J Cell Biol. 2003 Sep 1;162(5):909-18. doi: 10.1083/jcb.200305145. PMID:12952941 doi:http://dx.doi.org/10.1083/jcb.200305145
- ↑ Nakatsu F, Ohno H. Adaptor protein complexes as the key regulators of protein sorting in the post-Golgi network. Cell Struct Funct. 2003 Oct;28(5):419-29. PMID:14745134
- ↑ Huang F, Khvorova A, Marshall W, Sorkin A. Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference. J Biol Chem. 2004 Apr 16;279(16):16657-61. Epub 2004 Feb 25. PMID:14985334 doi:10.1074/jbc.C400046200
- ↑ Owen DJ, Collins BM, Evans PR. Adaptors for clathrin coats: structure and function. Annu Rev Cell Dev Biol. 2004;20:153-91. PMID:15473838 doi:10.1146/annurev.cellbio.20.010403.104543
- ↑ Paing MM, Johnston CA, Siderovski DP, Trejo J. Clathrin adaptor AP2 regulates thrombin receptor constitutive internalization and endothelial cell resensitization. Mol Cell Biol. 2006 Apr;26(8):3231-42. doi: 10.1128/MCB.26.8.3231-3242.2006. PMID:16581796 doi:http://dx.doi.org/10.1128/MCB.26.8.3231-3242.2006
- ↑ Lau AW, Chou MM. The adaptor complex AP-2 regulates post-endocytic trafficking through the non-clathrin Arf6-dependent endocytic pathway. J Cell Sci. 2008 Dec 15;121(Pt 24):4008-17. doi: 10.1242/jcs.033522. Epub 2008, Nov 25. PMID:19033387 doi:10.1242/jcs.033522
- ↑ Kuo AH, Stoica GE, Riegel AT, Wellstein A. Recruitment of insulin receptor substrate-1 and activation of NF-kappaB essential for midkine growth signaling through anaplastic lymphoma kinase. Oncogene. 2007 Feb 8;26(6):859-69. Epub 2006 Jul 31. PMID:16878150 doi:10.1038/sj.onc.1209840
- ↑ Federici M, Pandolfi A, De Filippis EA, Pellegrini G, Menghini R, Lauro D, Cardellini M, Romano M, Sesti G, Lauro R, Consoli A. G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation. 2004 Jan 27;109(3):399-405. Epub 2004 Jan 5. PMID:14707024 doi:10.1161/01.CIR.0000109498.77895.6F
- ↑ Choi E, Kikuchi S, Gao H, Brodzik K, Nassour I, Yopp A, Singal AG, Zhu H, Yu H. Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling. Nat Commun. 2019 Apr 1;10(1):1473. doi: 10.1038/s41467-019-09318-3. PMID:30931927 doi:http://dx.doi.org/10.1038/s41467-019-09318-3
|
