Home LiteratureArticle Details
PMID: 9736716 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Blocking ligand occupancy of the alphaVbeta3 integrin inhibits insulin-like growth factor I signaling in vascular smooth muscle cells.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 95 ·No. 19 ·1998-09-15 ·Pages 11217-22

Zheng B, Clemmons DR

Abstract

Blocking alphaVbeta3 integrin occupancy results in attenuation of the cellular migration response to insulin-like growth factor I (IGF-I). To determine whether integrin antagonists alter other IGF-I-stimulated biologic actions, quiescent smooth muscle cells (SMCs) were exposed to echistatin and their ability to respond to IGF-I was determined. Echistatin (10(-7) M) inhibited IGF-I-stimulated DNA synthesis by 80%, and the protein synthesis response also was inhibited. Therefore blocking occupancy of alphaVbeta3 inhibited multiple target cell actions of IGF-I. To determine whether blocking alphaVbeta3 occupancy could alter IGF-I receptor-mediated signal transduction, the ability of IGF-I to stimulate phosphorylation of insulin receptor substrate-1 (IRS-1) was analyzed. A 10-min exposure to 100 ng/ml of IGF-I resulted in a substantial increase in phosphorylated IRS-1, and echistatin (10(-7) M) blocked the IGF-I-induced IRS-1 phosphorylation response. Echistatin also attenuated downstream signaling because the capacity of the p85 subunit of phosphatidylinositol-3 kinase (PI-3 kinase) to bind to IRS-1 was blocked. In contrast, exposure of SMCs to vitronectin (1.0 micrograms/cm2) or thrombospondin (0.25 micrograms/cm2), two known ligands for alphaVbeta3, resulted in enhancement of the IGF-I-stimulated IRS-1 response. To determine whether these effects were caused by alterations in receptor kinase activity, the IGF-I receptor was immunoprecipitated and then analyzed for phosphotyrosine. Echistatin (10(-7) M) significantly reduced IGF-I-stimulated tyrosine phosphorylation of the IGF-I receptor beta subunit. We conclude that occupancy of the alphaVbeta3 integrin is necessary for IGF-I to fully activate the kinase activity of the IGF-I receptor and phosphorylate IRS-1. Activation of the alphaVbeta3 receptor results in an interaction with the IGF-I signal transduction pathway, which modulates SMCs responsiveness to IGF-I.

MeSH Terms
Animals Binding Sites/drug effects Cell Movement/drug effects Extracellular Matrix Proteins/pharmacology Insulin Receptor Substrate Proteins Insulin-Like Growth Factor I/pharmacology Intercellular Signaling Peptides and Proteins Ligands Muscle, Smooth, Vascular/physiology Nucleic Acid Synthesis Inhibitors/pharmacology Peptides/pharmacology Phosphatidylinositol 3-Kinases/metabolism Phosphoproteins/metabolism Phosphorylation/drug effects Phosphotyrosine/analysis Platelet-Derived Growth Factor/pharmacology Receptors, Vitronectin/antagonists & inhibitors Signal Transduction/drug effects Swine Thrombospondins/pharmacology Thymidine/metabolism Vitronectin/pharmacology
Chemicals
Extracellular Matrix Proteins Insulin Receptor Substrate Proteins Intercellular Signaling Peptides and Proteins Ligands Nucleic Acid Synthesis Inhibitors Peptides Phosphoproteins Platelet-Derived Growth Factor Receptors, Vitronectin Thrombospondins Vitronectin echistatin Phosphotyrosine Insulin-Like Growth Factor I Thymidine
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Zheng B
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Clemmons D R
References (38)
38 references, click to expand
  1. IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3'-kinase.
    Endocrinology. 1993 Apr;132(4):1421-30 PMID: 8384986
  2. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors.
    J Cell Biol. 1996 Dec;135(6 Pt 1):1633-42 PMID: 8978828
  3. Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques.
    J Clin Invest. 1993 Oct;92(4):1686-96 PMID: 8408622
  4. Dietary-induced atherosclerotic lesions have increased levels of acidic FGF mRNA and altered cytoskeletal and extracellular matrix mRNA expression.
    J Vasc Res. 1993 Nov-Dec;30(6):327-32 PMID: 7694665
  5. Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins.
    Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13612-7 PMID: 9391074
  6. Protease-resistant form of insulin-like growth factor-binding protein 5 is an inhibitor of insulin-like growth factor-I actions on porcine smooth muscle cells in culture.
    J Clin Invest. 1997 Nov 15;100(10):2596-605 PMID: 9366575
  7. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B.
    Science. 1998 Jan 30;279(5351):710-4 PMID: 9445477
  8. The effect of extracellular matrix proteins on porcine smooth muscle cell insulin-like growth factor (IGF) binding protein-5 synthesis and responsiveness to IGF-I.
    J Biol Chem. 1998 Apr 10;273(15):8994-9000 PMID: 9535886
  9. The smooth muscle cell. II. Growth of smooth muscle in culture and formation of elastic fibers.
    J Cell Biol. 1971 Jul;50(1):172-86 PMID: 4327464
  10. Interaction of circulating cell-derived and plasma growth factors in stimulating cultured smooth muscle cell replication.
    J Cell Physiol. 1984 Nov;121(2):425-30 PMID: 6386833
  11. Interaction of receptors for insulin-like growth factor I, platelet-derived growth factor, and fibroblast growth factor in rat aortic cells.
    Endocrinology. 1987 Jun;120(6):2251-8 PMID: 3032582
  12. Novel purification of vitronectin from human plasma by heparin affinity chromatography.
    Cell Struct Funct. 1988 Aug;13(4):281-92 PMID: 2460263
  13. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein.
    Nature. 1991 Jul 4;352(6330):73-7 PMID: 1648180
  14. Regulation of insulin-like growth factor I messenger RNA levels in vascular smooth muscle cells.
    Hypertension. 1991 Dec;18(6):742-7 PMID: 1743755
  15. In vivo proliferation of rat vascular smooth muscle in relation to diabetes mellitus insulin-like growth factor I and insulin.
    Diabetologia. 1992 Feb;35(2):104-8 PMID: 1312491
  16. Cloning and sequence determination of bovine insulin-like growth factor binding protein-2 (IGFBP-2): comparison of its structural and functional properties with IGFBP-1.
    J Cell Biochem. 1992 Feb;48(2):215-26 PMID: 1377702
  17. Posttranslational regulation of insulin-like growth factor binding protein-4 in normal and transformed human fibroblasts. Insulin-like growth factor dependence and biological studies.
    J Clin Invest. 1993 Mar;91(3):1129-37 PMID: 7680662
  18. The insulin signaling system.
    J Biol Chem. 1994 Jan 7;269(1):1-4 PMID: 8276779
  19. Inhibition of neointimal hyperplasia by blocking alpha V beta 3 integrin with a small peptide antagonist GpenGRGDSPCA.
    J Vasc Surg. 1994 Jan;19(1):125-34 PMID: 7508000
  20. Insulin-like growth factor-I and platelet-derived growth factor-BB induce directed migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation.
    J Clin Invest. 1994 Mar;93(3):1266-74 PMID: 8132765
  21. Involvement of phosphoinositide 3-kinase in insulin- or IGF-1-induced membrane ruffling.
    EMBO J. 1994 May 15;13(10):2313-21 PMID: 8194523
  22. Dynamic expression of alpha 1 beta 1 and alpha 2 beta 1 integrin receptors by human vascular smooth muscle cells. Alpha 2 beta 1 integrin is required for chemotaxis across type I collagen-coated membranes.
    Am J Pathol. 1994 Nov;145(5):1070-81 PMID: 7977639
  23. Stimulation of phosphatidylinositol 3'-kinase association with foca adhesion kinase by platelet-derived growth factor.
    J Biol Chem. 1994 Dec 9;269(49):31229-33 PMID: 7983066
  24. Association of insulin receptor substrate-1 with integrins.
    Science. 1994 Dec 2;266(5190):1576-8 PMID: 7527156
  25. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques.
    J Clin Invest. 1995 May;95(5):2266-74 PMID: 7738191
  26. Proteolytic cleavage of insulin-like growth factor binding protein 4 (IGFBP-4). Localization of cleavage site to non-homologous region of native IGFBP-4.
    J Biol Chem. 1995 May 12;270(19):11377-82 PMID: 7538115
  27. Insulin-like growth factors and their binding proteins: biological actions.
    Endocr Rev. 1995 Feb;16(1):3-34 PMID: 7758431
  28. Insulin-like growth factor (IGF)-binding proteins inhibit the smooth muscle cell migration responses to IGF-I and IGF-II.
    Endocrinology. 1995 Oct;136(10):4168-73 PMID: 7545099
  29. The insulin-like growth factor system in vascular smooth muscle: interaction with insulin and growth factors.
    Metabolism. 1995 Oct;44(10 Suppl 4):58-66 PMID: 7476313
  30. Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex.
    Mol Biol Cell. 1995 Oct;6(10):1349-65 PMID: 8573791
  31. Integrin-associated protein is a receptor for the C-terminal domain of thrombospondin.
    J Biol Chem. 1996 Jan 5;271(1):21-4 PMID: 8550562
  32. G-protein coupled and tyrosine kinase receptors: evidence that activation of the insulin-like growth factor I receptor is required for thrombin-induced mitogenesis of rat aortic smooth muscle cells.
    J Clin Invest. 1996 Jan 1;97(1):139-45 PMID: 8550825
  33. Ligand occupancy of the alpha-V-beta3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor.
    Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2482-7 PMID: 8637900
  34. Insulin-like growth factor-I (IGF-I) regulates IGF-binding protein-5 synthesis through transcriptional activation of the gene in aortic smooth muscle cells.
    J Biol Chem. 1996 Feb 23;271(8):4280-8 PMID: 8626775
  35. Thrombospondin modulates alpha v beta 3 function through integrin-associated protein.
    J Cell Biol. 1996 Oct;135(2):533-44 PMID: 8896608
  36. Signaling via the insulin-like growth factor-I receptor: does it differ from insulin receptor signaling?
    Cytokine Growth Factor Rev. 1996 Aug;7(2):153-9 PMID: 8899293
  37. Integrin cytoplasmic interactions and bidirectional transmembrane signalling.
    Curr Opin Cell Biol. 1996 Oct;8(5):657-69 PMID: 8939656
  38. Angiotensin II regulates insulin-like growth factor I gene expression in vascular smooth muscle cells.
    J Biol Chem. 1993 Aug 5;268(22):16866-70 PMID: 8344966
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.95.19.11217
Published
1998-09-15
Pages
11217-22
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC21622
Subset
IM
Grants
NHLBI NIH HHS · R01 HL056850 · United States
NHLBI NIH HHS · HL-56850 · United States
External Links
PubMed source DOI: 10.1073/pnas.95.19.11217 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