NDLI: The M-Ras-RA-GEF-2-Rap1 Pathway Mediates Tumor Necrosis Factor-α–dependent Regulation of Integrin Activation in Splenocytes

Content Provider	PubMed Central
Author	Yoshikawa, Yoko Satoh, Takaya Tamura, Takashi Wei, Ping Bilasy, Shymaa E. Edamatsu, Hironori Aiba, Atsu Katagiri, Koko Kinashi, Tatsuo Nakao, Kazuki Kataoka, Tohru
Editor	Richard, Assoian
Copyright Year	2007
Abstract	The Rap1 small GTPase has been implicated in regulation of integrin-mediated leukocyte adhesion downstream of various chemokines and cytokines in many aspects of inflammatory and immune responses. However, the mechanism for Rap1 regulation in the adhesion signaling remains unclear. RA-GEF-2 is a member of the multiple-member family of guanine nucleotide exchange factors (GEFs) for Rap1 and characterized by the possession of a Ras/Rap1-associating domain, interacting with M-Ras-GTP as an effector, in addition to the GEF catalytic domain. Here, we show that RA-GEF-2 is specifically responsible for the activation of Rap1 that mediates tumor necrosis factor-α (TNF-α)-triggered integrin activation. In BAF3 hematopoietic cells, activated M-Ras potently induced lymphocyte function–associated antigen 1 (LFA-1)-mediated cell aggregation. This activation was totally abrogated by knockdown of RA-GEF-2 or Rap1. TNF-α treatment activated LFA-1 in a manner dependent on M-Ras, RA-GEF-2, and Rap1 and induced activation of M-Ras and Rap1 in the plasma membrane, which was accompanied by recruitment of RA-GEF-2. Finally, we demonstrated that M-Ras and RA-GEF-2 were indeed involved in TNF-α–stimulated and Rap1-mediated LFA-1 activation in splenocytes by using mice deficient in RA-GEF-2. These findings proved a crucial role of the cross-talk between two Ras-family GTPases M-Ras and Rap1, mediated by RA-GEF-2, in adhesion signaling.
Related Links	http://dx.doi.org/10.1091/mbc.e07-03-0250
Ending Page	2959
Page Count	11
Starting Page	2949
File Format	PDF
ISSN	10591524
e-ISSN	19394586
Journal	Molecular Biology of the Cell
Issue Number	8
Volume Number	18
Language	English
Publisher	The American Society for Cell Biology
Publisher Date	2007-08-01
Access Restriction	Open
Rights Holder	The American Society for Cell Biology
Subject Keyword	Cell Biology Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology

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