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

J. Biol. Chem., Vol. 280, Issue 3, 1838-1848, January 21, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/3/1838    most recent M409466200v1 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 Gerasimovskaya, E. V. Articles by Stenmark, K. R. Search for Related Content PubMed PubMed Citation Articles by Gerasimovskaya, E. V. Articles by Stenmark, K. R. Social Bookmarking                      What's this?

Extracellular ATP-induced Proliferation of Adventitial Fibroblasts Requires Phosphoinositide 3-Kinase, Akt, Mammalian Target of Rapamycin, and p70 S6 Kinase Signaling Pathways^*

Evgenia V. Gerasimovskaya, Doug A. Tucker, Mary Weiser-Evans, Janet M. Wenzlau, Dwight J. Klemm¶, Mark Banks, and Kurt R. Stenmark

From the Developmental Lung Biology Laboratory and ^¶Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver, Colorado 80262

Extracellular nucleotides are increasingly recognized as important regulators of growth in a variety of cell types. Recent studies have demonstrated that extracellular ATP is a potent inducer of fibroblast growth acting, at least in part, through an ERK1/2-dependent signaling pathway. However, the contributions of additional signaling pathways to extracellular ATP-mediated cell proliferation have not been defined. By using both pharmacologic and genetic approaches, we found that in addition to ERK1/2, phosphatidylinositol 3-kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), and p70 S6K-dependent signaling pathways are required for ATP-induced proliferation of adventitial fibroblasts. We found that extracellular ATP acting in part through G_i proteins increased PI3K activity in a time-dependent manner and transient phosphorylation of Akt. This PI3K pathway is not involved in ATP-induced activation of ERK1/2, implying activation of independent parallel signaling pathways by ATP. Extracellular ATP induced dramatic increases in mTOR and p70 S6K phosphorylation. This activation of the mTOR/p70 S6 kinase (p70 S6K) pathway in response to ATP is because of independent contributions of PI3K/Akt and ERK1/2 pathways, which converge on the level of p70 S6K. ATP-dependent activation of mTOR and p70 S6K also requires additional signaling inputs perhaps from pathways operating through G or G subunits. Collectively, our data demonstrate that ATP-induced adventitial fibroblast proliferation requires activation and interaction of multiple signaling pathways such as PI3K, Akt, mTOR, p70 S6K, and ERK1/2 and provide evidence for purinergic regulation of the protein translational pathways related to cell proliferation.

Received for publication, August 17, 2004 , and in revised form, October 26, 2004.

^* This work was supported by National Institutes of Health Grants HL-57144 and HL-14985. Preliminary results of this work were presented at the XIII International Vascular Biology Meeting, May 12–16, 2002, Karuizawa, Japan, and at the American Thoracic Society Annual Meeting, May 18–23, 2002, Atlanta, GA. 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: 4200 East 9th Ave., University of Colorado Health Sciences Center, Research Bridge, B131, Denver, CO 80262. Tel.: 303-315-1193; Fax: 303-315-8353; E-mail: Evgenia.Gerasimovskaya{at}UCHSC.edu.

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

This article has been cited by other articles:

				W. Jiang, Z. Zhu, and H. J. Thompson Dietary Energy Restriction Modulates the Activity of AMP-Activated Protein Kinase, Akt, and Mammalian Target of Rapamycin in Mammary Carcinomas, Mammary Gland, and Liver Cancer Res., July 1, 2008; 68(13): 5492 - 5499. [Abstract] [Full Text] [PDF]

				K. R. Stenmark, K. A. Fagan, and M. G. Frid Hypoxia-Induced Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms Circ. Res., September 29, 2006; 99(7): 675 - 691. [Abstract] [Full Text] [PDF]

				H. Cao, N. Dronadula, and G. N. Rao Thrombin induces expression of FGF-2 via activation of PI3K-Akt-Fra-1 signaling axis leading to DNA synthesis and motility in vascular smooth muscle cells Am J Physiol Cell Physiol, January 1, 2006; 290(1): C172 - C182. [Abstract] [Full Text] [PDF]