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

J. Biol. Chem., Vol. 283, Issue 39, 26538-26547, September 26, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/39/26538    most recent M805611200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sai, J. Articles by Richmond, A. Search for Related Content PubMed PubMed Citation Articles by Sai, J. Articles by Richmond, A. Social Bookmarking                      What's this?

Parallel Phosphatidylinositol 3-Kinase (PI3K)-dependent and Src-dependent Pathways Lead to CXCL8-mediated Rac2 Activation and Chemotaxis^*

Jiqing Sai, Dayanidhi Raman, Yuxin Liu, John Wikswo, and Ann Richmond^¶1

From the ^¶Department of Veterans Affairs and Department of Cancer Biology, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232 and the VIIBRE and Biomedical Engineering, School of Engineering, Vanderbilt University, Nashville, Tennessee 37212

The requirement for phosphatidylinositol 3-kinase (PI3K) in the establishment of cell polarity and motility in a number of cell types has recently come into question. In this study, we demonstrate that inhibition of PI3K by wortmannin in neutrophil-like differentiated HL60 cells expressing CXCR2 resulted in reduced cell motility but normal chemotaxis in response to a gradient of CXCL8. However, wortmannin inhibition of PI3K did impair the ability of cells to re-orient their polarity and respond quickly to a change in the direction of the CXCL8 gradient. We hypothesized that Src-regulated ELMO-Dock2-Rac2 activation mediates chemotaxis in the absence of PI3K activity. Inhibition of Src with the small molecule inhibitor, PP2, or inhibition of Dock2 by shRNA knockdown confirmed the functional role of Src and Dock2 in regulating chemotaxis when PI3K was inhibited. Moreover, neutrophils isolated from bone marrow of hck^-/-fgr^-/-lyn^-/- mice exhibited much more severe inhibition of chemotaxis when PI3K was blocked with wortmannin as compared with neutrophils isolated from bone marrow of wild-type mice. Thus, PI3K and Src-ELMO-Dock2 pathways work in parallel to activate Rac2 and modulate chemotaxis in response to a CXCL8 gradient in neutrophils.

Received for publication, July 22, 2008

^* This work was supported, in whole or in part by National Institutes of Health Grants CA34590 (to A. R.) and NCI U54CA113007 (to Vito Quaranta). This work was also supported by a Senior Research Career Scientist Award from the Department of Veterans Affairs (to A. R.), the Vanderbilt Institute for Integrative Biosystems Research and Education and the Vanderbilt Academic Venture Capital Fund (to J. W.), and the Vanderbilt Ingram-Cancer Center Grant CA68485 (to Jennifer Pietenpol). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Movies S1–S4, Tables S1 and S2, and Figs. S1–S3.

¹ To whom correspondence should be addressed: Dept. of Cancer Biology, School of Medicine, Vanderbilt University, Nashville, TN 37232. Tel.: 615-343-7777; Fax: 615-936-2911; E-mail: ann.richmond{at}vanderbilt.edu.

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

This article has been cited by other articles:

				N. F. Neel, M. Barzik, D. Raman, T. Sobolik-Delmaire, J. Sai, A. J. Ham, R. L. Mernaugh, F. B. Gertler, and A. Richmond VASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis J. Cell Sci., June 1, 2009; 122(11): 1882 - 1894. [Abstract] [Full Text] [PDF]

				C. Cataisson, R. Ohman, G. Patel, A. Pearson, M. Tsien, S. Jay, L. Wright, H. Hennings, and S. H. Yuspa Inducible Cutaneous Inflammation Reveals a Protumorigenic Role for Keratinocyte CXCR2 in Skin Carcinogenesis Cancer Res., January 1, 2009; 69(1): 319 - 328. [Abstract] [Full Text] [PDF]