| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
Division of Endocrinology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7170
Address all correspondence and requests for reprints to: David R. Clemmons Division of Endocrinology, University of North Carolina, Chapel Hill, North Carolina 27599-7170. E-mail: dpm{at}med.unc.edu
Insulin-like growth factor-I (IGF-I) is a potent stimulator of vascular
smooth muscle cell (SMC) migration, a process that contributes to the
accumulation of SMC within atherosclerotic lesions. Our previous
studies have shown that IGF-I increases the affinity of the 
Vß3
integrin toward ligands and that occupancy of this integrin is
indispensable for IGF-I to stimulate cell migration. In this study, the
role of phosphatidylinositol 3-kinase (PI 3-kinase) and
mitogen-activated protein kinase (MAPK) pathways in IGF-I induced cell
motility and integrin activation was studied using porcine aortic
smooth muscle cells (pSMC). Two structurally different inhibitors of PI
3-kinase decreased IGF-I-stimulated pSMC migration in a dose-dependent
manner. The IC50 of wortmannin for inhibiting migration was
10 nM, and that of LY294002 was 0.3 µM. These
inhibitors also suppressed IGF-I-induced phosphorylation of protein
kinase B PKB/Akt at Ser437 using concentrations that also
inhibited cell motility. PD98059, an inhibitor of the MAPK pathway, was
somewhat less potent than PI 3-kinase inhibitors in blocking cell
migration that had been stimulated by IGF-I. When IGF-I increased
migration of pSMC 2.1-fold above control, 100 nM wortmannin
inhibited this response by 79%, 1 µM LY294002 inhibited
it by 58%, and 50 µM PD98059 caused a 34% reduction. In
comparison, 100 nM wortmannin inhibited IGF-I stimulated
DNA synthesis by 57%, 1 µM LY294002 inhibited it by
59%, whereas 50 µM PD98059 suppressed it completely.
Thus, activation of PI 3-kinase plays the major role in
IGF-I-stimulated migration and proliferation of pSMC. While the
activation of the MAPK pathway seems to be necessary for stimulation of
mitogenesis by IGF-I, the contribution of this pathway in IGF-I-induced
cell migration is limited in pSMC. Interestingly, neither PI 3-kinase
inhibitors nor PD98059 blocked the increase in Vß3 integrin
affinity that followed IGF-I treatment. Therefore, although both the PI
3-kinase and MAPK pathways were used by IGF-I to increase migration of
pSMC, Vß3 integrin activation did not depend on either PI 3-kinase
or MAPK activation, suggesting the possible importance of some other
signal transduction pathway to account for its full actions on pSMC.
This article has been cited by other articles:
 |
|
 |
|
  X. Shen, G. Xi, Y. Radhakrishnan, and D. R. Clemmons Identification of Novel SHPS-1-associated Proteins and Their Roles in Regulation of Insulin-like Growth Factor-dependent Responses in Vascular Smooth Muscle Cells Mol. Cell. Proteomics, July 1, 2009; 8(7): 1539 - 1551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Meng, D.-D. Lv, and J. Fang Insulin-like growth factor-I induces reactive oxygen species production and cell migration through Nox4 and Rac1 in vascular smooth muscle cells Cardiovasc Res, November 1, 2008; 80(2): 299 - 308. [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]
|
|
|
|
 |
|
 D. Zhuang, Q. Pu, B. Ceacareanu, Y. Chang, M. Dixit, and A. Hassid Chronic insulin treatment amplifies PDGF-induced motility in differentiated aortic smooth muscle cells by suppressing the expression and function of PTP1B Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H163 - H173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Radhakrishnan, L. A. Maile, Y. Ling, L. M. Graves, and D. R. Clemmons Insulin-like Growth Factor-I Stimulates Shc-dependent Phosphatidylinositol 3-Kinase Activation via Grb2-associated p85 in Vascular Smooth Muscle Cells J. Biol. Chem., June 13, 2008; 283(24): 16320 - 16331. [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, B. E. Capps, Y. Ling, G. Xi, and D. R. Clemmons Hyperglycemia Alters the Responsiveness of Smooth Muscle Cells to Insulin-Like Growth Factor-I Endocrinology, May 1, 2007; 148(5): 2435 - 2443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. M. Risinger Jr., T. S. Hunt, D. L. Updike, E. C. Bullen, and E. W. Howard Matrix Metalloproteinase-2 Expression by Vascular Smooth Muscle Cells Is Mediated by Both Stimulatory and Inhibitory Signals in Response to Growth Factors J. Biol. Chem., September 8, 2006; 281(36): 25915 - 25925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lieskovska, Y. Ling, J. Badley-Clarke, and D. R. Clemmons The Role of Src Kinase in Insulin-like Growth Factor-dependent Mitogenic Signaling in Vascular Smooth Muscle Cells J. Biol. Chem., September 1, 2006; 281(35): 25041 - 25053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kwintkiewicz, R. Z. Spaczynski, N. Foyouzi, T. Pehlivan, and A. J. Duleba Insulin and Oxidative Stress Modulate Proliferation of Rat Ovarian Theca-Interstitial Cells Through Diverse Signal Transduction Pathways Biol Reprod, June 1, 2006; 74(6): 1034 - 1040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Nigro, N. Osman, A. M. Dart, and P. J. Little Insulin Resistance and Atherosclerosis Endocr. Rev., May 1, 2006; 27(3): 242 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kwon, Y. Ling, L. A. Maile, J. Badley-Clark, and D. R. Clemmons Recruitment of the Tyrosine Phosphatase Src Homology 2 Domain Tyrosine Phosphatase-2 to the p85 Subunit of Phosphatidylinositol-3 (PI-3) Kinase Is Required for Insulin-Like Growth Factor-I-Dependent PI-3 Kinase Activation in Smooth Muscle Cells Endocrinology, March 1, 2006; 147(3): 1458 - 1465. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ling, L. A. Maile, J. Lieskovska, J. Badley-Clarke, and D. R. Clemmons Role of SHPS-1 in the Regulation of Insulin-like Growth Factor I-stimulated Shc and Mitogen-activated Protein Kinase Activation in Vascular Smooth Muscle Cells Mol. Biol. Cell, July 1, 2005; 16(7): 3353 - 3364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Li and B. E. Sumpio Strain-induced vascular endothelial cell proliferation requires PI3K-dependent mTOR-4E-BP1 signal pathway Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1591 - H1597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ling, L. A. Maile, J. Badley-Clarke, and D. R. Clemmons DOK1 Mediates SHP-2 Binding to the {alpha}V{beta}3 Integrin and Thereby Regulates Insulin-like Growth Factor I Signaling in Cultured Vascular Smooth Muscle Cells J. Biol. Chem., February 4, 2005; 280(5): 3151 - 3158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. White, R. G. Atrasz, E. G. Dickie, D. M. Aronoff, V. Stambolic, T. W. Mak, B. B. Moore, and M. Peters-Golden Prostaglandin E2 Inhibits Fibroblast Migration by E-Prostanoid 2 Receptor-Mediated Increase in PTEN Activity Am. J. Respir. Cell Mol. Biol., February 1, 2005; 32(2): 135 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Clemmons and L. A. Maile Interaction between Insulin-Like Growth Factor-I Receptor and {alpha}V{beta}3 Integrin Linked Signaling Pathways: Cellular Responses to Changes in Multiple Signaling Inputs Mol. Endocrinol., January 1, 2005; 19(1): 1 - 11. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zahradka, G. Harding, B. Litchie, S. Thomas, J. P. Werner, D. P. Wilson, and N. Yurkova Activation of MMP-2 in response to vascular injury is mediated by phosphatidylinositol 3-kinase-dependent expression of MT1-MMP Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2861 - H2870. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. G. Lechuga, Z. H. Hernandez-Nazara, J.-A. D. Rosales, E. R. Morris, A. R. Rincon, A. M. Rivas-Estilla, A. Esteban-Gamboa, and M. Rojkind TGF-{beta}1 modulates matrix metalloproteinase-13 expression in hepatic stellate cells by complex mechanisms involving p38MAPK, PI3-kinase, AKT, and p70S6k Am J Physiol Gastrointest Liver Physiol, November 1, 2004; 287(5): G974 - G987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dell'Agli, A. Busciala, and E. Bosisio Vascular effects of wine polyphenols Cardiovasc Res, September 1, 2004; 63(4): 593 - 602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Yao, Y. Chen, W. Zhai, K. Xu, W. L. Young, and G.-Y. Yang Minocycline Exerts Multiple Inhibitory Effects on Vascular Endothelial Growth Factor-Induced Smooth Muscle Cell Migration: The Role of ERK1/2, PI3K, and Matrix Metalloproteinases Circ. Res., August 20, 2004; 95(4): 364 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-L. Hu, R. G. Cowan, R. M. Harman, and S. M. Quirk Cell Cycle Progression and Activation of Akt Kinase Are Required for Insulin-Like Growth Factor I-Mediated Suppression of Apoptosis in Granulosa Cells Mol. Endocrinol., February 1, 2004; 18(2): 326 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B Gonzalez-Timon, M Gonzalez-Munoz, C Zaragoza, S Lamas, and E.M Melian Native and oxidized low density lipoproteins oppositely modulate the effects of insulin-like growth factor I on VSMC Cardiovasc Res, February 1, 2004; 61(2): 247 - 255. [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]
|
|
|
|
|
|
Y. Ling, L. A. Maile, and D. R. Clemmons Tyrosine Phosphorylation of the {beta}3-Subunit of the {alpha}V{beta}3 Integrin Is Required for Membrane Association of the Tyrosine Phosphatase SHP-2 and Its Further Recruitment to the Insulin-Like Growth Factor I Receptor Mol. Endocrinol., September 1, 2003; 17(9): 1824 - 1833. [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]
|
|
|
|
|
|
D. R. Clemmons and L. A. Maile Minireview: Integral Membrane Proteins that Function Coordinately with the Insulin-Like Growth Factor I Receptor to Regulate Intracellular Signaling Endocrinology, May 1, 2003; 144(5): 1664 - 1670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. R. Standley, A. Camaratta, B. P. Nolan, C. T. Purgason, and M. A. Stanley Cyclic stretch induces vascular smooth muscle cell alignment via NO signaling Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1907 - H1914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Askari, M. A. Carroll, M. Capparelli, F. Kramer, R. G. Gerrity, and K. E. Bornfeldt Oleate and Linoleate Enhance the Growth-promoting Effects of Insulin-like Growth Factor-I through a Phospholipase D-dependent Pathway in Arterial Smooth Muscle Cells J. Biol. Chem., September 20, 2002; 277(39): 36338 - 36344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Rebsamen, J. Sun, A. W. Norman, and J. K. Liao 1{alpha},25-Dihydroxyvitamin D3 Induces Vascular Smooth Muscle Cell Migration via Activation of Phosphatidylinositol 3-Kinase Circ. Res., July 12, 2002; 91(1): 17 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Iijima, M. Yoshizumi, M. Hashimoto, M. Akishita, K. Kozaki, J. Ako, T. Watanabe, Y. Ohike, B. Son, J. Yu, et al. Red Wine Polyphenols Inhibit Vascular Smooth Muscle Cell Migration Through Two Distinct Signaling Pathways Circulation, May 21, 2002; 105(20): 2404 - 2410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nam, A. Moralez, and D. Clemmons Vitronectin Binding to IGF Binding Protein-5 (IGFBP-5) Alters IGFBP-5 Modulation of IGF-I Actions Endocrinology, January 1, 2002; 143(1): 30 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. X.-D. Song, R. A. McPherson, L. Adam, Y. Bao, M. Shupnik, R. Kumar, and R. J. Santen Linkage of Rapid Estrogen Action to MAPK Activation by ER{alpha}-Shc Association and Shc Pathway Activation Mol. Endocrinol., January 1, 2002; 16(1): 116 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Gonzalez, S. Lamas, and E. M. Melian Cooperation between Low Density Lipoproteins and IGF-I in the Promotion of Mitogenesis in Vascular Smooth Muscle Cells Endocrinology, November 1, 2001; 142(11): 4852 - 4860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. P. Smith, A. Kamyar, W. Niu, J. Wang, B. Cercek, S. D. Chernausek, and J. A. Fagin IGF-Binding Protein-4 Expression and IGF-Binding Protein-4 Protease Activity Are Regulated Coordinately in Smooth Muscle During Postnatal Development and After Vascular Injury Endocrinology, October 1, 2001; 142(10): 4420 - 4427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. T. Gerthoffer and S. J. Gunst Signal Transduction in Smooth Muscle: Invited Review: Focal adhesion and small heat shock proteins in the regulation of actin remodeling and contractility in smooth muscle J Appl Physiol, August 1, 2001; 91(2): 963 - 972. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. A. Yamboliev, J. Chen, and W. T. Gerthoffer PI 3-kinases and Src kinases regulate spreading and migration of cultured VSMCs Am J Physiol Cell Physiol, August 1, 2001; 281(2): C709 - C718. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Poretsky, D. Seto-Young, A. Shrestha, S. Dhillon, M. Mirjany, H.-C. Liu, M. C Yih, and Z. Rosenwaks Phosphatidyl-Inositol-3 Kinase-Independent Insulin Action Pathway(s) in the Human Ovary J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3115 - 3119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Liu, Y. Liu, and W. L. Lowe Jr. The Role of Phosphatidylinositol 3-Kinase and the Mitogen-Activated Protein Kinases in Insulin-Like Growth Factor-I-Mediated Effects in Vascular Endothelial Cells Endocrinology, May 1, 2001; 142(5): 1710 - 1719. [Abstract] [Full Text]
|
|
|
|
|
|
J. J. Carrillo, B. Ibares, A. Esteban-Gamboa, and J. E. Feliu Involvement of Both Phosphatidylinositol 3-Kinase and p44/p42 Mitogen-Activated Protein Kinase Pathways in the Short-Term Regulation of Pyruvate Kinase L by Insulin Endocrinology, March 1, 2001; 142(3): 1057 - 1064. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Prasad, R. S. Topping, and S. J. Decker SH2-Containing Inositol 5'-Phosphatase SHIP2 Associates with the p130Cas Adapter Protein and Regulates Cellular Adhesion and Spreading Mol. Cell. Biol., February 15, 2001; 21(4): 1416 - 1428. [Abstract] [Full Text]
|
|
|
|
 |
|
 E. L. Greene, G. Lu, D. Zhang, and B. M. Egan Signaling Events Mediating the Additive Effects of Oleic Acid and Angiotensin II on Vascular Smooth Muscle Cell Migration Hypertension, February 1, 2001; 37(2): 308 - 312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Lehman, C. C. Paul, M. A. Baumann, and J. Gomez-Cambronero MAP kinase upregulation after hematopoietic differentiation: role of chemotaxis Am J Physiol Cell Physiol, January 1, 2001; 280(1): C183 - C191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Jung, J. Haendeler, C. Goebel, A. M. Zeiher, and S. Dimmeler Growth factor-induced phosphoinositide 3-OH kinase/Akt phosphorylation in smooth muscle cells: induction of cell proliferation and inhibition of cell death Cardiovasc Res, October 1, 2000; 48(1): 148 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Boney, P. A. Gruppuso, R. A. Faris, and A. R. Frackelton Jr. The Critical Role of Shc in Insulin-Like Growth Factor-I-Mediated Mitogenesis and Differentiation in 3T3-L1 Preadipocytes Mol. Endocrinol., June 1, 2000; 14(6): 805 - 813. [Abstract] [Full Text]
|
|
|
|
|
|
C. Duan, M. B. Liimatta, and O. L. Bottum Insulin-like Growth Factor (IGF)-I Regulates IGF-binding Protein-5 Gene Expression through the Phosphatidylinositol 3-Kinase, Protein Kinase B/Akt, and p70 S6 Kinase Signaling Pathway J. Biol. Chem., December 24, 1999; 274(52): 37147 - 37153. [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]
|
|
|
|
|
|
A. Kusch, S. Tkachuk, H. Haller, R. Dietz, D. C. Gulba, M. Lipp, and I. Dumler Urokinase Stimulates Human Vascular Smooth Muscle Cell Migration via a Phosphatidylinositol 3-Kinase-Tyk2 Interaction J. Biol. Chem., December 8, 2000; 275(50): 39466 - 39473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Wu, W.-L. Lee, Y. Y. Wu, D. Chen, T.-J. Liu, A. Jang, P. M. Sharma, and P. H. Wang Expression of Constitutively Active Phosphatidylinositol 3-Kinase Inhibits Activation of Caspase 3 and Apoptosis of Cardiac Muscle Cells J. Biol. Chem., December 15, 2000; 275(51): 40113 - 40119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Qi, S. Ikematsu, N. Maeda, K. Ichihara-Tanaka, S. Sakuma, M. Noda, T. Muramatsu, and K. Kadomatsu Haptotactic Migration Induced by Midkine. INVOLVEMENT OF PROTEIN-TYROSINE PHOSPHATASE zeta , MITOGEN-ACTIVATED PROTEIN KINASE, AND PHOSPHATIDYLINOSITOL 3-KINASE J. Biol. Chem., May 4, 2001; 276(19): 15868 - 15875. [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]
|
|
|
|
|
|
W. Zhang, B. Razani, Y. Altschuler, B. Bouzahzah, K. E. Mostov, R. G. Pestell, and M. P. Lisanti Caveolin-1 Inhibits Epidermal Growth Factor-stimulated Lamellipod Extension and Cell Migration in Metastatic Mammary Adenocarcinoma Cells (MTLn3). TRANSFORMATION SUPPRESSOR EFFECTS OF ADENOVIRUS-MEDIATED GENE DELIVERY OF CAVEOLIN-1 J. Biol. Chem., June 30, 2000; 275(27): 20717 - 20725. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
