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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 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 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 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. Related Collections Hematopoiesis and Stem Cells Cell Adhesion and Motility Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 June 2003, Vol. 101, No. 12, pp. 4725-4732 HEMATOPOIESIS Genetic evidence for convergence of c-Kit– and 4 integrin–mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells Bai Lin Tan, Mustafa N. Yazicioglu, David Ingram, Jennifer McCarthy, Jovencio Borneo, David A. Williams, and Reuben Kapur From the Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN; and the Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. Mast cells play a critical role in host defense against a number of pathogens. Increased mast cell infiltration has been described in allergic asthma, in rheumatoid arthritis, and during helminthes infection. Despite the importance of mast cells in allergic disease and defense against infection, little is known about the mechanisms 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 a small G protein, Rac, was observed in mast cells derived from class IA phosphoinositide-3 kinase (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 small G protein, Rac2. In addition, a PI-3kinase inhibitor inhibited 4- as well as SCF-induced migration in a dose-dependent fashion. In contrast, a mitogen-activated protein kinase (MAPK) 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 that 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. Kapur Genetic and pharmacologic evidence implicating the p85{alpha}, but not p85{beta}, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis Blood, September 1, 2007; 110(5): 1612 - 1620. [Abstract] [Full Text] [PDF] L. A. Samayawardhena, R. Kapur, and A. W. B. Craig Involvement of Fyn kinase in Kit and integrin-mediated Rac activation, cytoskeletal reorganization, and chemotaxis of mast cells Blood, May 1, 2007; 109(9): 3679 - 3686. [Abstract] [Full Text] [PDF] V. Dolgachev, M. Thomas, A. Berlin, and N. W. Lukacs Stem cell factor-mediated activation pathways promote murine eosinophil CCL6 production and survival J. Leukoc. Biol., April 1, 2007; 81(4): 1111 - 1119. [Abstract] [Full Text] [PDF] W. F. Khalaf, F.-C. Yang, S. Chen, H. White, W. Bessler, D. A. Ingram, and D. W. 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Rivera IgE-dependent Activation of Sphingosine Kinases 1 and 2 and Secretion of Sphingosine 1-Phosphate Requires Fyn Kinase and Contributes to Mast Cell Responses J. Biol. Chem., February 3, 2006; 281(5): 2515 - 2525. [Abstract] [Full Text] [PDF] T. Oki, J. Kitaura, K. Eto, Y. Lu, M. Maeda-Yamamoto, N. Inagaki, H. Nagai, Y. Yamanishi, H. Nakajina, H. Kumagai, et al. Integrin {alpha}IIb{beta}3 Induces the Adhesion and Activation of Mast Cells through Interaction with Fibrinogen J. Immunol., January 1, 2006; 176(1): 52 - 60. [Abstract] [Full Text] [PDF] V. Munugalavadla, L. C. Dore, B. L. Tan, L. Hong, M. Vishnu, M. J. Weiss, and R. Kapur Repression of c-Kit and Its Downstream Substrates by GATA-1 Inhibits Cell Proliferation during Erythroid Maturation Mol. Cell. Biol., August 1, 2005; 25(15): 6747 - 6759. [Abstract] [Full Text] [PDF] V. Munugalavadla, J. Borneo, D. A. Ingram, and R. Kapur p85{alpha} subunit of class IA PI-3 kinase is crucial for macrophage growth and migration Blood, July 1, 2005; 106(1): 103 - 109. [Abstract] [Full Text] [PDF] J. P. Abonia, K. F. Austen, B. J. Rollins, S. K. Joshi, R. A. Flavell, W. A. Kuziel, P. A. Koni, and M. F. Gurish Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2 Blood, June 1, 2005; 105(11): 4308 - 4313. [Abstract] [Full Text] [PDF] M. Jansen, F.-C. Yang, J. A. Cancelas, J. R. Bailey, and D. A. Williams Rac2-Deficient Hematopoietic Stem Cells Show Defective Interaction with the Hematopoietic Microenvironment and Long-Term Engraftment Failure Stem Cells, March 1, 2005; 23(3): 335 - 346. [Abstract] [Full Text] [PDF] J. Lennartsson, T. Jelacic, D. Linnekin, and R. Shivakrupa Normal and Oncogenic Forms of the Receptor Tyrosine Kinase Kit Stem Cells, January 1, 2005; 23(1): 16 - 43. [Abstract] [Full Text] [PDF] K. Hiatt, D. A. Ingram, H. Huddleston, D. F. Spandau, R. Kapur, and D. W. Clapp Loss of the Nf1 Tumor Suppressor Gene Decreases Fas Antigen Expression in Myeloid Cells Am. J. Pathol., April 1, 2004; 164(4): 1471 - 1479. [Abstract] [Full Text] [PDF] J. L. Pennock and R. K. Grencis In vivo exit of c-kit+/CD49dhi/{beta}7+ mucosal mast cell precursors from the bone marrow following infection with the intestinal nematode Trichinella spiralis Blood, April 1, 2004; 103(7): 2655 - 2660. [Abstract] [Full Text] [PDF]

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