HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 41, 42709-42718, October 8, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/41/42709    most recent M404480200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qiao, M. Articles by Passaniti, A. Search for Related Content PubMed PubMed Citation Articles by Qiao, M. Articles by Passaniti, A. Social Bookmarking                      What's this?

Insulin-like Growth Factor-1 Regulates Endogenous RUNX2 Activity in Endothelial Cells through a Phosphatidylinositol 3-Kinase/ERK-dependent and Akt-independent Signaling Pathway^*

Meng Qiao, Paul Shapiro, Rakesh Kumar, and Antonino Passaniti¶||

From the Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, Department of Cellular and Molecular Oncology, M. D. Anderson Cancer Center, Houston, Texas 77030, and ^¶Departments of Pathology and Biochemistry & Molecular Biology, Greenebaum Cancer Center Program in Oncology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Insulin-like growth factor-1 (IGF-1) is an angiogenic and oncogenic factor that activates signal transduction pathways involved in the expression of transcriptional regulators of tumorigenesis. RUNX2, a member of the Ig-loop family of transcription factors is expressed in vascular endothelial cells (EC) and regulates EC migration, invasion, and proliferation. Here we show that IGF-1 and its receptor regulate post-translational changes in RUNX2 to activate DNA binding in proliferating EC. The phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, reduced both basal and IGF-1-stimulated RUNX2 DNA binding activity in the absence of changes in RUNX2 protein as did the overexpression of the phosphatidylinositol 3-phosphate phosphatase, confirming that PI3K signaling mediates RUNX2 activation. IGF-1 increased ERK1/2 activation, which was abrogated by the inhibition of PI3K, thus linking these two pathways in EC. Treatment with U0126, which inhibits ERK1/2 activation, reduced IGF-1-stimulated RUNX2 DNA binding without affecting RUNX2 protein levels. Overexpression of constitutively active MKK1 increased RUNX2 DNA binding and phosphorylation. No additive effects of PI3K or ERK inhibitors on DNA binding were evident. Surprisingly, these IGF-1-mediated effects on RUNX2 were not regulated by Akt phosphorylation, a common downstream target of PI3K, as determined by pharmacological or genetic inhibition. However, an inhibitor of the p21-activated protein kinase-1, glutathione S-transferase-Pak1-(83–149), inhibited both basal and IGF-1-stimulated RUNX2 DNA binding, suggesting that Pak1 mediates IGF-1 signaling to increase RUNX2 activity. These results indicate that the angiogenic growth factor, IGF-1, can regulate RUNX2 DNA binding through sequential activation of the PI3K/Pak1 and ERK1/2 signaling cascade.

Received for publication, April 22, 2004 , and in revised form, August 2, 2004.

^* This work was supported in part by American Heart Association Grant 0151434U (to A. P.) and National Institutes of Health Grants CA95350 (to A. P.) and CA90970 (to R. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: The University of Maryland School of Medicine, Greenebaum Cancer Center, Bressler Research Bldg. 7-021, 655 W. Baltimore St., Baltimore, MD 21201. Tel.: 410-328-5470; Fax: 410-328-6559; E-mail: apass001{at}umaryland.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Sampaio, M. Dance, A. Montagner, T. Edouard, N. Malet, B. Perret, A. Yart, J.-P. Salles, and P. Raynal Signal Strength Dictates Phosphoinositide 3-Kinase Contribution to Ras/Extracellular Signal-Regulated Kinase 1 and 2 Activation via Differential Gab1/Shp2 Recruitment: Consequences for Resistance to Epidermal Growth Factor Receptor Inhibition Mol. Cell. Biol., January 15, 2008; 28(2): 587 - 600. [Abstract] [Full Text] [PDF]

				C. J. Rosen Circulating IGF-I and Bone Remodeling: New Insights into Old Questions IBMS BoneKEy, January 1, 2008; 5(1): 7 - 15. [Abstract] [Full Text] [PDF]

				Y. C. Levine, G. K. Li, and T. Michel Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells: EVIDENCE FOR AN AMPK -> Rac1 -> Akt -> ENDOTHELIAL NITRIC-OXIDE SYNTHASE PATHWAY J. Biol. Chem., July 13, 2007; 282(28): 20351 - 20364. [Abstract] [Full Text] [PDF]

				T. Isayeva, D. Chanda, L. Kallman, I.-E. A. Eltoum, and S. Ponnazhagan Effects of Sustained Antiangiogenic Therapy in Multistage Prostate Cancer in TRAMP Model Cancer Res., June 15, 2007; 67(12): 5789 - 5797. [Abstract] [Full Text] [PDF]

				T. Nguyen, J. Chai, A. Li, T. Akahoshi, T. Tanigawa, and A. S. Tarnawski Novel Roles of Local Insulin-Like Growth Factor-1 Activation in Gastric Ulcer Healing: Promotes Actin Polymerization, Cell Proliferation, Re-Epithelialization, and Induces Cyclooxygenase-2 in a Phosphatidylinositol 3-Kinase-Dependent Manner Am. J. Pathol., April 1, 2007; 170(4): 1219 - 1228. [Abstract] [Full Text] [PDF]

				C. Ge, G. Xiao, D. Jiang, and R. T. Franceschi Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development J. Cell Biol., February 26, 2007; 176(5): 709 - 718. [Abstract] [Full Text] [PDF]

				M. Qiao, P. Shapiro, M. Fosbrink, H. Rus, R. Kumar, and A. Passaniti Cell Cycle-dependent Phosphorylation of the RUNX2 Transcription Factor by cdc2 Regulates Endothelial Cell Proliferation J. Biol. Chem., March 17, 2006; 281(11): 7118 - 7128. [Abstract] [Full Text] [PDF]

				A. Vivacqua, D. Bonofiglio, A. G. Recchia, A. M. Musti, D. Picard, S. Ando, and M. Maggiolini The G Protein-Coupled Receptor GPR30 Mediates the Proliferative Effects Induced by 17{beta}-Estradiol and Hydroxytamoxifen in Endometrial Cancer Cells Mol. Endocrinol., March 1, 2006; 20(3): 631 - 646. [Abstract] [Full Text] [PDF]

				N. N. Johnson-Farley, T. Travkina, and D. S. Cowen Cumulative Activation of Akt and Consequent Inhibition of Glycogen Synthase Kinase-3 by Brain-Derived Neurotrophic Factor and Insulin-Like Growth Factor-1 in Cultured Hippocampal Neurons J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1062 - 1069. [Abstract] [Full Text] [PDF]

				A. B. Celil and P. G. Campbell BMP-2 and Insulin-like Growth Factor-I Mediate Osterix (Osx) Expression in Human Mesenchymal Stem Cells via the MAPK and Protein Kinase D Signaling Pathways J. Biol. Chem., September 9, 2005; 280(36): 31353 - 31359. [Abstract] [Full Text] [PDF]

				J. P. Stains and R. Civitelli Gap Junctions Regulate Extracellular Signal-regulated Kinase Signaling to Affect Gene Transcription Mol. Biol. Cell, January 1, 2005; 16(1): 64 - 72. [Abstract] [Full Text] [PDF]