Journal
JOURNAL OF IMMUNOLOGY
Volume 179, Issue 12, Pages 8322-8331Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.179.12.8322
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Funding
- NCI NIH HHS [CA108647, R01 CA108647-03, R01 CA108647] Funding Source: Medline
- NHLBI NIH HHS [HL69974, R01 HL070259, P01 HL069974, R01 HL077177, R01 HL081092, R01 HL070259-04, R01 HL081092-01A2] Funding Source: Medline
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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 Rop1a(-/-) 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 Ib are not functionally redundant but rather differentially regulate certain cellular events.
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