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Molecular and Cellular Biology, August 2000, p. 6074-6083, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Rap2 as a Slowly Responding Molecular Switch in the Rap1 Signaling Cascade

Yusuke Ohba,1,2 Naoki Mochizuki,1 Keiko Matsuo,1 Shigeko Yamashita,1 Mie Nakaya,1 Yuko Hashimoto,3 Michinari Hamaguchi,4 Takeshi Kurata,3 Kazuo Nagashima,2 and Michiyuki Matsuda1,*

Department of Pathology, Research Institute, International Medical Center of Japan, Shinjuku-ku, Tokyo 162-8655,1 Department of Pathology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640,3 Department of Molecular Pathogenesis, Nagoya University School of Medicine, Nagoya 466-8550,4 and Laboratory of Molecular and Cellular Pathology, Hokkaido University School of Medicine, Sapporo 060-8638,2 Japan

Received 29 December 1999/Returned for modification 8 February 2000/Accepted 8 May 2000

Rap2 is a member of the Ras family of GTPases and exhibits 60% identity to Rap1, but the function and regulation of Rap2 remain obscure. We found that, unlike the other Ras family proteins, the GTP-bound active form exceeded 50% of total Rap2 protein in adherent cells. Guanine nucleotide exchange factors (GEFs) for Rap1, C3G, Epac (or cyclic AMP [cAMP]-GEF), CalDAG-GEFI, PDZ-GEF1, and GFR efficiently increased the level of GTP-Rap2 both in 293T cells and in vitro. GTPase-activating proteins (GAPs) for Rap1, rap1GAPII and SPA-1, stimulated Rap2 GTPase, but with low efficiency. The half-life of GTP-Rap2 was significantly longer than that of GTP-Rap1 in 293T cells, indicating that low sensitivity to GAPs caused a high GTP/GDP ratio on Rap2. Rap2 bound to the Ras-binding domain of Raf and inhibited Ras-dependent activation of Elk1 transcription factor, as did Rap1. The level of GTP-Rap2 in rat 3Y1 fibroblasts was decreased by the expression of v-Src, and expression of a GTPase-deficient Rap2 mutant inhibited v-Src-dependent transformation of 3Y1 cells. Altogether, Rap2 is regulated by a similar set of GEFs and GAPs as Rap1 and functions as a slowly responding molecular switch in the Rap1 signaling cascade.

* Corresponding author. Mailing address: Department of Pathology, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. Phone: 81-3-3202-7181, ext. 2833. Fax: 81-3-3205-1236. E-mail: mmatsuda{at}ri.imcj.go.jp.

Molecular and Cellular Biology, August 2000, p. 6074-6083, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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