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Molecular and Cellular Biology, June 2001, p. 3671-3683, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3671-3683.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cyclic AMP-Mediated Inhibition of Cell Growth Requires the Small G Protein Rap1

John M. Schmitt and Philip J. S. Stork*

Vollum Institute, Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, Oregon 97201

Received 2 February 2001/Returned for modification 27 February 2001/Accepted 9 March 2001

In many normal and transformed cell types, the intracellular second messenger cyclic AMP (cAMP) blocks the effects of growth factors and serum on mitogenesis, proliferation, and cell cycle progression. cAMP exerts these growth-inhibitory effects via inhibition of the mitogen-activated protein (MAP) kinase cascade. Here, using Hek293 and NIH 3T3 cells, we show that cAMP's inhibition of the MAP kinase cascade is mediated by the small G protein Rap1. Activation of Rap1 by cAMP induces the association of Rap1 with Raf-1 and limits Ras-dependent activation of ERK. In NIH 3T3 cells, Rap1 is required not only for cAMP's inhibition of ERK activation but for inhibition of cell proliferation and mitogenesis as well.

* Corresponding author. Mailing address: Vollum Institute, L474, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201-3098 Phone: (503) 494-5494. Fax: (503) 494-4976. E-mail: stork{at}ohsu.edu.

Molecular and Cellular Biology, June 2001, p. 3671-3683, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3671-3683.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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