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Rap1a Null Mice Have Altered Myeloid Cell Functions Suggesting Distinct Roles for the Closely Related Rap1a and 1b Proteins¹

Yu Li^2,*,¶, Jingliang Yan^*,¶, Pradip De^||, Hua-Chen Chang^,,, Akira Yamauchi, Kent W. Christopherson, II^**, Nivanka C. Paranavitana^3,*,¶, Xiaodong Peng, Chaekyun Kim^,#, Veerendra Munugulavadla, Reuben Kapur^*,,, Hanying Chen, Weinian Shou^*,, James C. Stone, Mark H. Kaplan^,,, Mary C. Dinauer^,,, Donald L. Durden^|| and Lawrence A. Quilliam^4,*,¶

^* Department of Biochemistry and Molecular Biology, Department of Microbiology and Immunology, Department of Pediatrics, Medical and Molecular Genetics, and Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; ^¶ Walther Cancer Institute, Indianapolis, IN 46208; ^|| Aflac Cancer Center and Blood Disorders, Department of Pediatrics, Emory University, Atlanta, GA 30322; ^# Inha University College of Medicine, Incheon, Korea; ^** Rush University Medical Center, Chicago, IL 60612; and Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada

The Ras-related GTPases Rap1a and 1b have been implicated in multiple biological events including cell adhesion, free radical production, and cancer. To gain a better understanding of Rap1 function in mammalian physiology, we deleted the Rap1a gene. Although loss of Rap1a expression did not initially affect mouse size or viability, upon backcross into C57BL/6J mice some Rap1a^–/– embryos died in utero. T cell, B cell, or myeloid cell development was not disrupted in Rap1a ^–/– mice. However, macrophages from Rap1a null mice exhibited increased haptotaxis on fibronectin and vitronectin matrices that correlated with decreased adhesion. Chemotaxis of lymphoid and myeloid cells in response to CXCL12 or CCL21 was significantly reduced. In contrast, an increase in FcR-mediated phagocytosis was observed. Because Rap1a was previously copurified with the human neutrophil NADPH oxidase, we addressed whether GTPase loss affected superoxide production. Neutrophils from Rap1a^–/– mice had reduced fMLP-stimulated superoxide production as well as a weaker initial response to phorbol ester. These results suggest that, despite 95% amino acid sequence identity, similar intracellular distribution, and broad tissue distribution, Rap1a and 1b are not functionally redundant but rather differentially regulate certain cellular events.

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 by an Indiana University School of Medicine Biomedical Research Grant, the Indiana Genomics Initiative of Indiana University, supported in part by Lilly Endowment Incorporated, and by National Institutes of Health Grants CA108647 and HL69974 (all to L.A.Q.). Y.L. was supported by American Heart Association predoctoral fellowship 0110245Z.

² Current address: Amgen, One Amgen Center Drive Thousand Oaks, CA 91302.

³ Current address: Applied Biosystems, 2130 Woodward Street, Austin, TX 78744.

⁴ Address correspondence and reprint requests to Dr. Lawrence A. Quilliam, Department of Biochemistry and Molecular Biology, 635 Barnhill Drive, MS-4053, Indiana University School of Medicine, Indianapolis, IN 46202. E-mail address: lquillia{at}iupui.edu

⁵ Abbreviations used in this paper: GEF, guanine nucleotide exchange factor; GAP, GTPase activating protein; ES cells, embryonic stem cells; KO, knockout; WT, wild type; MEF, mouse embryo fibroblast; BMD, bone marrow-derived;

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