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* Laboratory of Molecular Immunology,
Laboratory of Platelet,
Vascular Signaling, Blood Research Institute, and
Division of Neoplastic Diseases and Related Disorders, Department of Medicine, and Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226
Rap1 is a small GTPase that belongs to Ras superfamily. This ubiquitously expressed GTPase is a key regulator of integrin functions. Rap1 exists in two isoforms: Rap1a and Rap1b. Although Rap1 has been extensively studied, its isoform-specific functions in B cells have not been elucidated. In this study, using gene knockout mice, we show that Rap1b is the dominant isoform in B cells. Lack of Rap1b significantly reduced the absolute number of B220+IgM– pro/pre-B cells and B220+IgM+ immature B cells in bone marrow. In vitro culture of bone marrow-derived Rap1b–/– pro/pre-B cells with IL-7 showed similar proliferation levels but reduced adhesion to stromal cell line compared with wild type. Rap1b–/– mice displayed reduced splenic marginal zone (MZ) B cells, and increased newly forming B cells, whereas the number of follicular B cells was normal. Functionally, Rap1b–/– mice showed reduced T-dependent but normal T-independent humoral responses. B cells from Rap1b–/– mice showed reduced migration to SDF-1, CXCL13 and in vivo homing to lymph nodes. MZ B cells showed reduced sphingosine-1-phosphate-induced migration and adhesion to ICAM-1. However, absence of Rap1b did not affect splenic B cell proliferation, BCR-mediated activation of Erk1/2, p38 MAPKs, and AKT. Thus, Rap1b is crucial for early B cell development, MZ B cell homeostasis and T-dependent humoral immunity.
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.
1 This work was supported in part by an American Cancer Society Scholar Grant RSG-02-172-LIB (to S.M.), by Roche Organ Transplantation Research Foundation Grant 111662730 (to S.M.), by National Institutes of Health Grants R01 A1064826-01 (to S.M.), U19 AI062627-01 (to S.M.), NO1-HHSN26600500032C (to S.M.), and HL-45100 (to G.C.W.), and by American Heart Association Grant SDG0235127N (to M.C.W.). H.C. is a recipient of Wisconsin Breast Cancer Show House Postdoctoral Fellowship. S.M. is a recipient of The American Society for Blood and Marrow Transplantation Young Investigator Award.
2 Address correspondence and reprint requests to Dr. Subramaniam Malarkannan, Laboratory of Molecular Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail address: subra.malar{at}bcw.edu
3 Abbreviations used in this paper: GEF, guanine nucleotide exchange factor; GAP, GTPase-activating protein; MZ, marginal zone; FO, follicular; TNP, trinitrophenol; KLH, keyhole limpet hemocyanin; S1P, sphingosine-1-phosphate; SDF, stromal cell-derived factor; LN, lymph node; WT, wild type.
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  Y. Katayama, M. Sekai, M. Hattori, I. Miyoshi, Y. Hamazaki, and N. Minato Rap signaling is crucial for the competence of IL-7 response and the development of B-lineage cells Blood, August 27, 2009; 114(9): 1768 - 1775. [Abstract] [Full Text] [PDF]
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