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MBC in Press, published online ahead of print May 30, 2007
Mol. Biol. Cell 10.1091/mbc.E07-03-0250

A more recent version of this article appeared on August 1, 2007
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Submitted on March 16, 2007
Revised on May 14, 2007
Accepted on May 18, 2007

The M-Ras-RA-GEF-2-Rap1 Pathway Mediates Tumor Necrosis Factor-{alpha}-dependent Regulation of Integrin Activation in Splenocytes

Yoko Yoshikawa,* Takaya Satoh,* Takashi Tamura,* Ping Wei,* Shymaa E. Bilasy,* Hironori Edamatsu,* Atsu Aiba,{dagger} Koko Katagiri,{ddagger} Tatsuo Kinashi,{ddagger} Kazuki Nakao,{sect} and Tohru Kataoka*

*Division of Molecular Biology, Department of Biochemistry and Molecular Biology, and {dagger}Division of Molecular Genetics, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; {ddagger}Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka 570-8506, Japan; {sect}Laboratory of Animal Resources and Genetic Engineering, Riken Center for Developmental Biology, Kobe 650-0047, Japan

Monitoring Editor: Richard Assoian

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-{alpha} (TNF-{alpha})-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-{alpha} 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-{alpha}-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.

Address correspondence to: Tohru Kataoka (kataoka{at}people.kobe-u.ac.jp)




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