Home LiteratureArticle Details
PMID: 11997497 Published · ppublish English Journal Article

APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes.

Molecular and cellular biology ·Vol. 22 ·No. 11 ·2002-06-00 ·Pages 3599-609

Liu J, Kimura A, Baumann CA, Saltiel AR

Abstract

APS is a Cbl-binding protein that is tyrosine phosphorylated by the insulin receptor kinase. Insulin-stimulated phosphorylation of tyrosine 618 in APS is necessary for its association with c-Cbl and the subsequent tyrosine phosphorylation of Cbl by the insulin receptor in both 3T3-L1 adipocytes and CHO-IR cells. When overexpressed in these cells, wild-type APS but not an APS/Y(618)F mutant facilitated the tyrosine phosphorylation of coexpressed Cbl and its association with Crk upon insulin stimulation. APS-facilitated phosphorylation occurred on tyrosines 371, 700, and 774 in the Cbl protein. APS also interacted directly with the c-Cbl-associated protein (CAP) and colocalized with the protein in cells. The association was dependent on the SH3 domains of CAP and was independent of insulin treatment. Overexpression of the APS/Y(618)F mutant in 3T3-L1 adipocytes blocked the insulin-stimulated tyrosine phosphorylation of endogenous Cbl and binding to Crk. Moreover, the translocation of GLUT4 from intracellular vesicles to the plasma membrane was also inhibited by overexpression of the APS/Y(618)F mutant. These data suggest that APS serves as an adapter protein linking the CAP/Cbl pathway to the insulin receptor and, further, that APS-facilitated Cbl tyrosine phosphorylation catalyzed by the insulin receptor is a crucial event in the stimulation of glucose transport by insulin.

MeSH Terms
3T3 Cells Adaptor Proteins, Signal Transducing Adipocytes/cytology,drug effects,metabolism Animals Biological Transport, Active/drug effects CHO Cells Cell Differentiation Cricetinae Glucose/metabolism Glucose Transporter Type 4 Insulin/pharmacology Mice Monosaccharide Transport Proteins/metabolism Muscle Proteins Mutagenesis, Site-Directed Phosphorylation Proteins/genetics,metabolism Proto-Oncogene Proteins/chemistry,metabolism Proto-Oncogene Proteins c-cbl Proto-Oncogene Proteins c-crk Receptor, Insulin/metabolism Transfection Tyrosine/chemistry Ubiquitin-Protein Ligases
Chemicals
Adaptor Proteins, Signal Transducing Glucose Transporter Type 4 Insulin Monosaccharide Transport Proteins Muscle Proteins Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-crk Sh2b2 protein, mouse Slc2a4 protein, mouse Tyrosine Proto-Oncogene Proteins c-cbl Ubiquitin-Protein Ligases Receptor, Insulin CBL protein, human Cbl protein, mouse Glucose
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Liu Jun
Department of Internal Medicine and Physiology, Life Science Institute, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Kimura Akiko
Baumann Christian A
Saltiel Alan R
References (45)
45 references, click to expand
  1. Thiazolidinediones and insulin resistance: peroxisome proliferatoractivated receptor gamma activation stimulates expression of the CAP gene.
    Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14751-6 PMID: 9843961
  2. A beta 1 integrin signaling pathway involving Src-family kinases, Cbl and PI-3 kinase is required for macrophage spreading and migration.
    EMBO J. 1998 Aug 3;17(15):4391-403 PMID: 9687507
  3. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1.
    Mol Cell. 1999 Dec;4(6):1029-40 PMID: 10635327
  4. Identification and characterization of novel substrates of Trk receptors in developing neurons.
    Neuron. 1998 Nov;21(5):1017-29 PMID: 9856458
  5. Mutations of the serine phosphorylated in the protein phosphatase-1-binding motif in the skeletal muscle glycogen-targeting subunit.
    Biochem J. 2000 Feb 15;346 Pt 1:77-82 PMID: 10657242
  6. Cloning and characterization of human Lnk, an adaptor protein with pleckstrin homology and Src homology 2 domains that can inhibit T cell activation.
    J Immunol. 2000 May 15;164(10):5199-206 PMID: 10799879
  7. The APS adapter protein couples the insulin receptor to the phosphorylation of c-Cbl and facilitates ligand-stimulated ubiquitination of the insulin receptor.
    FEBS Lett. 2000 Jun 9;475(1):31-4 PMID: 10854852
  8. The proto-oncogene c-Cbl is a positive regulator of Met-induced MAP kinase activation: a role for the adaptor protein Crk.
    Oncogene. 2000 Aug 17;19(35):4058-65 PMID: 10962563
  9. CAP defines a second signalling pathway required for insulin-stimulated glucose transport.
    Nature. 2000 Sep 14;407(6801):202-7 PMID: 11001060
  10. RING finger proteins: mediators of ubiquitin ligase activity.
    Cell. 2000 Sep 1;102(5):549-52 PMID: 11007473
  11. SH2-B and APS are multimeric adapters that augment TrkA signaling.
    Mol Cell Biol. 2001 Mar;21(5):1613-20 PMID: 11238898
  12. Cbl: many adaptations to regulate protein tyrosine kinases.
    Nat Rev Mol Cell Biol. 2001 Apr;2(4):294-307 PMID: 11283727
  13. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10.
    Nature. 2001 Apr 19;410(6831):944-8 PMID: 11309621
  14. The sorbin homology domain: a motif for the targeting of proteins to lipid rafts.
    Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9098-103 PMID: 11481476
  15. Acquisition of increased hormone sensitivity during in vitro adipocyte development.
    J Biol Chem. 1977 May 25;252(10):3554-7 PMID: 193837
  16. v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas.
    Proc Natl Acad Sci U S A. 1989 Feb;86(4):1168-72 PMID: 2784003
  17. The sequences of the human and mouse c-cbl proto-oncogenes show v-cbl was generated by a large truncation encompassing a proline-rich domain and a leucine zipper-like motif.
    Oncogene. 1991 Apr;6(4):653-7 PMID: 2030914
  18. Ligand-induced polyubiquitination of receptor tyrosine kinases.
    Biochem Biophys Res Commun. 1995 Aug 4;213(1):32-9 PMID: 7639752
  19. Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation.
    J Biol Chem. 1995 Sep 1;270(35):20242-5 PMID: 7657591
  20. The protein product of the c-cbl oncogene rapidly complexes with the EGF receptor and is tyrosine phosphorylated following EGF stimulation.
    Oncogene. 1995 Oct 19;11(8):1561-7 PMID: 7478580
  21. Cbl: complex formation and functional implications.
    Cell Signal. 1998 Jun;10(6):377-85 PMID: 9720760
  22. MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade.
    Science. 1998 Sep 11;281(5383):1668-71 PMID: 9733512
  23. A mammalian scaffold complex that selectively mediates MAP kinase activation.
    Science. 1998 Sep 11;281(5383):1671-4 PMID: 9733513
  24. SH2-Balpha is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase.
    Biochem J. 1998 Oct 1;335 ( Pt 1):103-9 PMID: 9742218
  25. Cloning and characterization of Lnk, a signal transduction protein that links T-cell receptor activation signal to phospholipase C gamma 1, Grb2, and phosphatidylinositol 3-kinase.
    Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11618-22 PMID: 8524815
  26. c-Cbl is transiently tyrosine-phosphorylated, ubiquitinated, and membrane-targeted following CSF-1 stimulation of macrophages.
    J Biol Chem. 1996 Jan 5;271(1):17-20 PMID: 8550554
  27. Physical and functional association of the cbl protooncogen product with an src-family protein tyrosine kinase, p53/56lyn, in the B cell antigen receptor-mediated signaling.
    J Exp Med. 1996 Feb 1;183(2):675-80 PMID: 8627181
  28. The two major sites of cbl tyrosine phosphorylation in abl-transformed cells select the crkL SH2 domain.
    Oncogene. 1996 May 2;12(9):1981-9 PMID: 8649859
  29. Ras-dependent, Ca2+-stimulated activation of nuclear factor of activated T cells by a constitutively active Cbl mutant in T cells.
    J Biol Chem. 1997 Jan 3;272(1):168-73 PMID: 8995243
  30. The proto-oncogene product p120(cbl) links c-Src and phosphatidylinositol 3'-kinase to the integrin signaling pathway.
    J Biol Chem. 1997 Feb 7;272(6):3780-7 PMID: 9013636
  31. Insulin stimulates tyrosine phosphorylation of the proto-oncogene product of c-Cbl in 3T3-L1 adipocytes.
    Biochem J. 1997 Jun 15;324 ( Pt 3):839-45 PMID: 9210408
  32. Insulin-stimulated tyrosine phosphorylation of caveolin is specific for the differentiated adipocyte phenotype in 3T3-L1 cells.
    J Biol Chem. 1997 Aug 15;272(33):20706-14 PMID: 9252391
  33. c-Cbl is tyrosine-phosphorylated by interleukin-4 and enhances mitogenic and survival signals of interleukin-4 receptor by linking with the phosphatidylinositol 3'-kinase pathway.
    Blood. 1998 Jan 1;91(1):46-53 PMID: 9414268
  34. A novel, multifuntional c-Cbl binding protein in insulin receptor signaling in 3T3-L1 adipocytes.
    Mol Cell Biol. 1998 Feb;18(2):872-9 PMID: 9447983
  35. A role for CAP, a novel, multifunctional Src homology 3 domain-containing protein in formation of actin stress fibers and focal adhesions.
    J Biol Chem. 1998 Feb 13;273(7):4073-80 PMID: 9461600
  36. Fyn, Yes, and Syk phosphorylation sites in c-Cbl map to the same tyrosine residues that become phosphorylated in activated T cells.
    J Biol Chem. 1998 Apr 3;273(14):8323-31 PMID: 9525940
  37. Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases.
    J Biol Chem. 1998 Apr 10;273(15):8867-74 PMID: 9535867
  38. The c-Cbl oncoprotein.
    Int J Biochem Cell Biol. 1998 Apr;30(4):439-44 PMID: 9675877
  39. Cbl-mediated negative regulation of the Syk tyrosine kinase. A critical role for Cbl phosphotyrosine-binding domain binding to Syk phosphotyrosine 323.
    J Biol Chem. 1998 Dec 25;273(52):35273-81 PMID: 9857068
  40. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase.
    Nat Genet. 1999 Feb;21(2):230-5 PMID: 9988280
  41. APS, an adaptor protein containing PH and SH2 domains, is associated with the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis.
    Oncogene. 1999 Jan 21;18(3):759-67 PMID: 9989826
  42. Identification of the APS protein as a novel insulin receptor substrate.
    J Biol Chem. 1999 Apr 16;274(16):11186-93 PMID: 10196204
  43. Synip: a novel insulin-regulated syntaxin 4-binding protein mediating GLUT4 translocation in adipocytes.
    Mol Cell. 1999 Jun;3(6):751-60 PMID: 10394363
  44. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase.
    Science. 1999 Oct 8;286(5438):309-12 PMID: 10514377
  45. Involvement of Shc and Cbl-PI 3-kinase in Lyn-dependent proliferative signaling pathways for G-CSF.
    Oncogene. 2000 Jan 6;19(1):97-105 PMID: 10644984
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.11.3599-3609.2002
Published
2002-06-00
Pages
3599-609
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC133825
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.22.11.3599-3609.2002 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2