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Prepublished online as a Blood First Edition Paper on January 30, 2003; DOI 10.1182/blood-2002-08-2521. This Article Full Text (PDF) All Versions of this Article: 2002-08-2521v1 101/12/4725    most recent Alert me when this article is cited Alert me if a correction is posted 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tan, B. L. Articles by Kapur, R. Search for Related Content PubMed PubMed Citation Articles by Tan, B. L. Articles by Kapur, R. Social Bookmarking                   What's this? Submitted August 16, 2002 Accepted December 12, 2002 Genetic evidence for convergence of c-Kit and 4 integrin-mediated signals on class IA PI-3kinase and Rac pathway in regulating integrin directed migration in mast cells Bai Lin Tan, M N Yazicioglu, David Ingram, Jennifer McCarthy, Jovencio Borneo, David A Williams, and Reuben Kapur* Section of Neonatal-Perinatal Medicine, Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA * Corresponding author; email: rkapur{at}iupui.edu. Mast cells play a critical role in host defense against a number of pathogens. Increased mast cell infiltration has been described in allergic asthma, rheumatoid arthritis and during helminthes infection. Despite the importance of mast cells in allergic disease and defense against infection, little is known about the mechanism(s) by which mast cells migrate to various tissues under steady state conditions or during infection or inflammation. Here, we show that activation of c-Kit by its ligand, stem cell factor (SCF) cooperates with 4 integrin in inducing directed migration of mast cells on fibronectin. A reduction in migration and activation of Rho GTPase Rac was observed in mast cells derived from class IA PI-3Kinase-deficient mice in response to SCF stimulation and in mast cells expressing the dominant negative Rac (RacN17), as well as in mast cells deficient in the hematopoietic specific Rho GTPase, Rac2. In addition, a PI-3Kinase inhibitor inhibited 4 as well as SCF-induced migration in a dose-dependent fashion. In contrast, a MEK inhibitor had little effect. Consistent with the pharmacologic results, abrogating the binding of the p85 subunit of class IA PI-3Kinase to c-Kit also resulted in inhibition of SCF-induced migration on fibronectin. These genetic and biochemical data demonstrate both c-Kit and 4 integrin signaling are linked to class IA PI-3Kinase and Rac pathways and regulate integrin directed (haptotactic) migration in mast cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. A. Knight, J. K. Brown, S. H. Wright, E. M. Thornton, J. A. Pate, and H. R.P. Miller Aberrant Mucosal Mast Cell Protease Expression in the Enteric Epithelium of Nematode-Infected Mice Lacking the Integrin {alpha}v{beta}6, a Transforming Growth Factor-{beta}1 Activator Am. J. Pathol., October 1, 2007; 171(4): 1237 - 1248. [Abstract] [Full Text] [PDF] V. Munugalavadla, E. C. Sims, J. Borneo, R. J. Chan, and R. 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