Rac2 regulates neutrophil chemotaxis, superoxide production, and myeloid colony formation through multiple distinct effector pathways

Dirk Carstanjen, Akira Yamauchi, Annemart Koornneef, Heesuk Zang, Marie Dominique Filippi, Chad Harris, Jason Towe, Simon Atkinson, Yi Zheng, Mary C. Dinauer, David A. Williams

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Polymorphonuclear neutrophils (PMN) are an important component of the innate immune system. We have shown previously that migration and superoxide (O2.-) production, as well as some kinase signaling pathways are compromised in mice deficient in the Ras-related Rho GTPase Rac2. In this study, we demonstrate that Rac2 controls chemotaxis and superoxide production via distinct pathways and is critical for development of myeloid colonies in vitro. The Rac2 mutants V36A, F37A, and N39A all bind to both Pak1 and p67phox, yet are unable to rescue superoxide production and chemotaxis when expressed in Rac2-/- PMN. In contrast, the N43A mutant, which binds to Por1 (Arfaptin 2), p67phox, and Pak1, is able to rescue superoxide production but not chemotaxis. The F37A mutant, demonstrated to have reduced binding to Por1, shows reduced rescue of fMLP-induced chemotaxis. Finally, the Rac2Y40C mutant that is defective in binding to all three potential downstream effectors (Pak1, p67phox, and Por1) is unable to rescue chemotaxis, motility, or superoxide production, but is able to rescue defective growth of myeloid colonies in vitro. These findings suggest that binding to any single effector is not sufficient to rescue the distinct cellular phenotypes of Rac2-/- PMN, implicating multiple, distinct, and potentially parallel effector pathways.

Original languageEnglish
Pages (from-to)4613-4620
Number of pages8
JournalJournal of Immunology
Volume174
Issue number8
DOIs
StatePublished - Apr 15 2005
Externally publishedYes

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    Carstanjen, D., Yamauchi, A., Koornneef, A., Zang, H., Filippi, M. D., Harris, C., Towe, J., Atkinson, S., Zheng, Y., Dinauer, M. C., & Williams, D. A. (2005). Rac2 regulates neutrophil chemotaxis, superoxide production, and myeloid colony formation through multiple distinct effector pathways. Journal of Immunology, 174(8), 4613-4620. https://doi.org/10.4049/jimmunol.174.8.4613