Endocrinology, Vol 136, 4168-4173, Copyright © 1995 by Endocrine Society

ARTICLES

Insulin-like growth factor (IGF)-binding proteins inhibit the smooth muscle cell migration responses to IGF-I and IGF-II

A Gockerman, T Prevette, JI Jones and DR Clemmons
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill 27599, USA.

Smooth muscle cells have been shown to migrate in response to insulin- like growth factor I (IGF-I). However, the role of IGF-binding proteins (IGFBPs) in this process has not been determined. As IGFBPs are synthesized and secreted by smooth muscle cells and bind to IGFs with high affinity, this study was undertaken to determine the ability of IGFBP-1 and -2 to modulate cellular migration in response to IGF-I and - II. Confluent monolayers of porcine vascular smooth muscle cells were wounded with a razor blade. After wounding, IGF-I and -II induced increases of 159 +/- 49% (mean +/- SD) and 108 +/- 33%, respectively, above control values in the number of cells migrating over a fixed distance in 4 days. The addition of IGFBP-1 caused a 19-21% inhibition of IGF-I- or IGF-II-stimulated migration, whereas the addition of IGFBP- 2 inhibited the effect of both by greater than 60%. The addition of IGFBP-2 alone had no effect, whereas IGFBP-1 addition was associated with a 42 +/- 12% increase. In contrast, [Trp221]IGFBP-1 in which the RGD sequence was changed to WGD, thus eliminating its capacity to bind to the alpha 5 beta 1 integrin, inhibited IGF-I-stimulated migration by 67 +/- 17%. An IGF analog that has a reduced affinity for IGFBP-2- stimulated migration equally well as IGF-I alone even in the presence of IGFBP-2. Likewise, the addition of insulin, which cannot bind to IGFBPs, at supraphysiological concentrations that are adequate to activate the IGF-I receptor resulted in a similar increase in migration. In summary, IGF-I and -II stimulate smooth muscle cell migration after wounding. This migratory response is modulated by IGFBPs. Both IGFBP-1 and IGFBP-2 appear to neutralize the effects of the IGFs by inhibiting their interaction with IGF receptors, but IGFBP- 1 also has a direct stimulatory effect that requires an intact RGD integrin recognition sequence.

This article has been cited by other articles:

				D. M. Breen, K. K. Chan, J. K. Dhaliwall, M. R. Ward, N. Al Koudsi, L. Lam, M. De Souza, H. Ghanim, P. Dandona, D. J. Stewart, et al. Insulin Increases Reendothelialization and Inhibits Cell Migration and Neointimal Growth After Arterial Injury Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1060 - 1066. [Abstract] [Full Text] [PDF]

				L. A. Maile, B. E. Capps, E. C. Miller, A. W. Aday, and D. R. Clemmons Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo Diabetes, October 1, 2008; 57(10): 2637 - 2643. [Abstract] [Full Text] [PDF]

				G. Xi, X. Shen, and D. R. Clemmons p66shc Negatively Regulates Insulin-Like Growth Factor I Signal Transduction via Inhibition of p52shc Binding to Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 Leading to Impaired Growth Factor Receptor-Bound Protein-2 Membrane Recruitment Mol. Endocrinol., September 1, 2008; 22(9): 2162 - 2175. [Abstract] [Full Text] [PDF]

				T. C. Nichols, W. H. Busby Jr., E. Merricks, J. Sipos, M. Rowland, K. Sitko, and D. R. Clemmons Protease-Resistant Insulin-Like Growth Factor (IGF)-Binding Protein-4 Inhibits IGF-I Actions and Neointimal Expansion in a Porcine Model of Neointimal Hyperplasia Endocrinology, October 1, 2007; 148(10): 5002 - 5010. [Abstract] [Full Text] [PDF]

				L. A. Maile, W. H. Busby, K. Sitko, B. E. Capps, T. Sergent, J. Badley-Clarke, Y. Ling, and D. R. Clemmons The Heparin Binding Domain of Vitronectin Is the Region that Is Required to Enhance Insulin-Like Growth Factor-I Signaling Mol. Endocrinol., April 1, 2006; 20(4): 881 - 892. [Abstract] [Full Text] [PDF]

				Y. Ma, L. Zhang, T. Peng, J. Cheng, S. Taneja, J. Zhang, P. Delafontaine, and J. Du Angiotensin II Stimulates Transcription of Insulin-Like Growth Factor I Receptor in Vascular Smooth Muscle Cells: Role of Nuclear Factor-{kappa}B Endocrinology, March 1, 2006; 147(3): 1256 - 1263. [Abstract] [Full Text] [PDF]

				L. A. Maile, W. H. Busby, K. Sitko, B. E. Capps, T. Sergent, J. Badley-Clarke, and D. R. Clemmons Insulin-Like Growth Factor-I Signaling in Smooth Muscle Cells Is Regulated by Ligand Binding to the 177CYDMKTTC184 Sequence of the {beta}3-Subunit of {alpha}V{beta}3 Mol. Endocrinol., February 1, 2006; 20(2): 405 - 413. [Abstract] [Full Text] [PDF]

				J. Cosin-Sales, J. C. Kaski, M. Christiansen, P. Kaminski, C. Oxvig, M. T. Overgaard, D. Cole, and D. W. Holt Relationship among pregnancy associated plasma protein-A levels, clinical characteristics, and coronary artery disease extent in patients with chronic stable angina pectoris Eur. Heart J., October 2, 2005; 26(20): 2093 - 2098. [Abstract] [Full Text] [PDF]

				A. Sala, S. Capaldi, M. Campagnoli, B. Faggion, S. Labo, M. Perduca, A. Romano, M. E. Carrizo, M. Valli, L. Visai, et al. Structure and Properties of the C-terminal Domain of Insulin-like Growth Factor-binding Protein-1 Isolated from Human Amniotic Fluid J. Biol. Chem., August 19, 2005; 280(33): 29812 - 29819. [Abstract] [Full Text] [PDF]

				K. Kaushal, A. H. Heald, K. W. Siddals, M. S. Sandhu, D. B. Dunger, J. M. Gibson, and N. J. Wareham The Impact of Abnormalities in IGF and Inflammatory Systems on the Metabolic Syndrome Diabetes Care, November 1, 2004; 27(11): 2682 - 2688. [Abstract] [Full Text] [PDF]

				K. W. Siddals, E. Marshman, M. Westwood, and J. M. Gibson Abrogation of Insulin-like Growth Factor-I (IGF-I) and Insulin Action by Mevalonic Acid Depletion: SYNERGY BETWEEN PROTEIN PRENYLATION AND RECEPTOR GLYCOSYLATION PATHWAYS J. Biol. Chem., September 10, 2004; 279(37): 38353 - 38359. [Abstract] [Full Text] [PDF]

				Q. Xu, S. Li, Y. Zhao, T. J. Maures, P. Yin, and C. Duan Evidence That IGF Binding Protein-5 Functions as a Ligand-Independent Transcriptional Regulator in Vascular Smooth Muscle Cells Circ. Res., March 19, 2004; 94(5): e46 - e54. [Abstract] [Full Text] [PDF]

				P. Delafontaine, Y.-H. Song, and Y. Li Expression, Regulation, and Function of IGF-1, IGF-1R, and IGF-1 Binding Proteins in Blood Vessels Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 435 - 444. [Abstract] [Full Text]

				L. A. Maile and D. R. Clemmons Integrin-Associated Protein Binding Domain of Thrombospondin-1 Enhances Insulin-Like Growth Factor-I Receptor Signaling in Vascular Smooth Muscle Cells Circ. Res., November 14, 2003; 93(10): 925 - 931. [Abstract] [Full Text] [PDF]

				T. Hsieh, R. E. Gordon, D. R. Clemmons, W. H. Busby Jr., and C. Duan Regulation of Vascular Smooth Muscle Cell Responses to Insulin-like Growth Factor (IGF)-I by Local IGF-binding Proteins J. Biol. Chem., October 31, 2003; 278(44): 42886 - 42892. [Abstract] [Full Text] [PDF]

				L. A. Maile, J. Badley-Clarke, and D. R. Clemmons The Association between Integrin-associated Protein and SHPS-1 Regulates Insulin-like Growth Factor-I Receptor Signaling in Vascular Smooth Muscle Cells Mol. Biol. Cell, September 1, 2003; 14(9): 3519 - 3528. [Abstract] [Full Text] [PDF]

				J. A. Kricker, C. L. Towne, S. M. Firth, A. C. Herington, and Z. Upton Structural and Functional Evidence for the Interaction of Insulin-Like Growth Factors (IGFs) and IGF Binding Proteins with Vitronectin Endocrinology, July 1, 2003; 144(7): 2807 - 2815. [Abstract] [Full Text] [PDF]

				S. M. Firth and R. C. Baxter Cellular Actions of the Insulin-Like Growth Factor Binding Proteins Endocr. Rev., December 1, 2002; 23(6): 824 - 854. [Abstract] [Full Text] [PDF]

				L. A. Maile and D. R. Clemmons The {alpha}V{beta}3 Integrin Regulates Insulin-Like Growth Factor I (IGF-I) Receptor Phosphorylation by Altering the Rate of Recruitment of the Src-Homology 2-Containing Phosphotyrosine Phosphatase-2 to the Activated IGF-I Receptor Endocrinology, November 1, 2002; 143(11): 4259 - 4264. [Abstract] [Full Text] [PDF]

				A. Jacob, J. D. Molkentin, A. Smolenski, S. M. Lohmann, and N. Begum Insulin inhibits PDGF-directed VSMC migration via NO/ cGMP increase of MKP-1 and its inactivation of MAPKs Am J Physiol Cell Physiol, September 1, 2002; 283(3): C704 - C713. [Abstract] [Full Text] [PDF]

				X. Zhang and D. Yee Insulin-like Growth Factor Binding Protein-1 (IGFBP-1) Inhibits Breast Cancer Cell Motility Cancer Res., August 1, 2002; 62(15): 4369 - 4375. [Abstract] [Full Text] [PDF]

				L. A. Maile and D. R. Clemmons Regulation of Insulin-like Growth Factor I Receptor Dephosphorylation by SHPS-1 and the Tyrosine Phosphatase SHP-2 J. Biol. Chem., March 8, 2002; 277(11): 8955 - 8960. [Abstract] [Full Text] [PDF]

				S. Zaina, L. Pettersson, B. Ahren, L. Branen, A. B. Hassan, M. Lindholm, R. Mattsson, J. Thyberg, and J. Nilsson Insulin-like Growth Factor II Plays a Central Role in Atherosclerosis in a Mouse Model J. Biol. Chem., February 1, 2002; 277(6): 4505 - 4511. [Abstract] [Full Text] [PDF]

				A. Bayes-Genis, R. S. Schwartz, D. A. Lewis, M. T. Overgaard, M. Christiansen, C. Oxvig, K. Ashai, D. R. Holmes Jr, and C. A. Conover Insulin-Like Growth Factor Binding Protein-4 Protease Produced by Smooth Muscle Cells Increases in the Coronary Artery After Angioplasty Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 335 - 341. [Abstract] [Full Text] [PDF]

				L. Maile, J Badley-Clarke, and D. Clemmons Structural analysis of the role of the (&bgr;)3 subunit of the (&agr;)V(&bgr;)3 integrin in IGF-I signaling J. Cell Sci., January 4, 2001; 114(7): 1417 - 1425. [Abstract] [PDF]

				K. Sakai, A. J. D'Ercole, L. J. Murphy, and D. R. Clemmons Physiological Differences in Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) Phosphorylation in IGFBP-1 Transgenic Mice Diabetes, January 1, 2001; 50(1): 32 - 38. [Abstract] [Full Text]

				A. Bayes-Genis, C. A. Conover, and R. S. Schwartz The Insulin-Like Growth Factor Axis : A Review of Atherosclerosis and Restenosis Circ. Res., February 4, 2000; 86(2): 125 - 130. [Abstract] [Full Text] [PDF]

				C. Duan, J. R. Bauchat, and T. Hsieh Phosphatidylinositol 3-Kinase Is Required for Insulin-Like Growth Factor-I-Induced Vascular Smooth Muscle Cell Proliferation and Migration Circ. Res., January 7, 2000; 86(1): 15 - 23. [Abstract] [Full Text] [PDF]

				A. M. Kahn, J. C. Allen, C. L. Seidel, and S. Zhang Insulin Inhibits Migration of Vascular Smooth Muscle Cells With Inducible Nitric Oxide Synthase Hypertension, January 1, 2000; 35(1): 303 - 306. [Abstract] [Full Text] [PDF]

				R. A. Frost and C. H. Lang Differential Effects of Insulin-Like Growth Factor I (IGF-I) and IGF-Binding Protein-1 on Protein Metabolism in Human Skeletal Muscle Cells Endocrinology, September 1, 1999; 140(9): 3962 - 3970. [Abstract] [Full Text]

				Y. Imai and D. R. Clemmons Roles of Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase Pathways in Stimulation of Vascular Smooth Muscle Cell Migration and Deoxyriboncleic Acid Synthesis by Insulin-Like Growth Factor-I Endocrinology, September 1, 1999; 140(9): 4228 - 4235. [Abstract] [Full Text]

				C. Rees, D. R. Clemmons, G. D. Horvitz, J. B. Clarke, and W. H. Busby A Protease-Resistant Form of Insulin-Like Growth Factor (IGF) Binding Protein 4 Inhibits IGF-1 Actions Endocrinology, October 1, 1998; 139(10): 4182 - 4188. [Abstract] [Full Text] [PDF]

				B. Zheng and D. R. Clemmons Blocking ligand occupancy of the alpha Vbeta 3 integrin inhibits insulin-like growth factor I signaling in vascular smooth muscle cells PNAS, September 15, 1998; 95(19): 11217 - 11222. [Abstract] [Full Text] [PDF]

				C. Duan and D. R. Clemmons Differential Expression and Biological Effects of Insulin-like Growth Factor-binding Protein-4 and -5 in Vascular Smooth Muscle Cells J. Biol. Chem., July 3, 1998; 273(27): 16836 - 16842. [Abstract] [Full Text] [PDF]

				B. Zheng, C. Duan, and D. R. Clemmons 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., April 10, 1998; 273(15): 8994 - 9000. [Abstract] [Full Text] [PDF]

				C. K. Abrass, A. K. Berfield, and D. L. Andress Heparin binding domain of insulin-like growth factor binding protein-5 stimulates mesangial cell migration Am J Physiol Renal Physiol, December 1, 1997; 273(6): F899 - F906. [Abstract] [Full Text] [PDF]

				D.-S. Suh and M. M. Rechler Hepatocyte Nuclear Factor 1 and the Glucocorticoid Receptor Synergistically Activate Transcription of the Rat Insulin-like Growth Factor Binding Protein-1 Gene Mol. Endocrinol., November 1, 1997; 11(12): 1822 - 1831. [Abstract] [Full Text]

				C. Duan, S. B. Hawes, T. Prevette, and D. R. Clemmons 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., February 23, 1996; 271(8): 4280 - 4288. [Abstract] [Full Text] [PDF]

				M. E. Doerr and J. I. Jones The Roles of Integrins and Extracellular Matrix Proteins in the Insulin-like Growth Factor I-stimulated Chemotaxis of Human Breast Cancer Cells J. Biol. Chem., February 2, 1996; 271(5): 2443 - 2447. [Abstract] [Full Text] [PDF]

				K. J. Scheidegger, R. W. James, and P. Delafontaine Differential Effects of Low Density Lipoproteins on Insulin-like Growth Factor-1 (IGF-1) and IGF-1 Receptor Expression in Vascular Smooth Muscle Cells J. Biol. Chem., August 25, 2000; 275(35): 26864 - 26869. [Abstract] [Full Text] [PDF]

				K. Sakai, W. H. Busby Jr., J. B. Clarke, and D. R. Clemmons Tissue Transglutaminase Facilitates the Polymerization of Insulin-like Growth Factor-binding Protein-1 (IGFBP-1) and Leads to Loss of IGFBP-1's Ability to Inhibit Insulin-like Growth Factor-I-stimulated Protein Synthesis J. Biol. Chem., March 16, 2001; 276(12): 8740 - 8745. [Abstract] [Full Text] [PDF]

				L. A. Maile, Y. Imai, J. B. Clarke, and D. R. Clemmons Insulin-like Growth Factor I Increases alpha Vbeta 3 Affinity by Increasing the Amount of Integrin-associated Protein That Is Associated with Non-raft Domains of the Cellular Membrane J. Biol. Chem., January 11, 2002; 277(3): 1800 - 1805. [Abstract] [Full Text] [PDF]