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Molecular and Cellular Biology, June 2003, p. 3735-3752, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.3735-3752.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

p27Kip1 Inhibition of GRB2-SOS Formation Can Regulate Ras Activation

Stephanie J. Moeller,1 Elizabeth D. Head,2,{dagger} and Robert J. Sheaff1,2,3*

University of Minnesota Cancer Center,1 Department of Biochemistry, Molecular Biology, and Biophysics,2 Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota 554553

Received 4 December 2002/ Returned for modification 30 January 2003/ Accepted 12 March 2003

p27Kip1 (p27) is often inappropriately downregulated in aggressive human cancers. Although p27 can inhibit cyclin-dependent kinases (CDKs), low p27 does not always correlate with increased CDK activity. Furthermore, cells derived from p27-/- mice respond to antimitogens, maintain restriction point control, and do not deregulate CDKs. Thus, disruption of a p27 function other than CDK inhibition may contribute to the disease state. A yeast two-hybrid screen identified growth factor receptor-bound protein 2 (GRB2) as a p27 binding partner. We now demonstrate that p27 can inhibit GRB2 function by blocking its association with the guanine nucleotide exchange factor SOS. Endogenous p27 is rapidly exported from the nucleus to the cytoplasm in response to mitogen stimulation, where it binds GRB2 concomitant with a decrease in GRB2-associated SOS. As predicted, mitogen-stimulated p27-/- cells maintained their GRB2-SOS complexes for significantly longer. The Ras/mitogen-activated protein kinase pathway does not appear to be deregulated in cells lacking p27 despite excess GRB2-SOS, suggesting that additional control mechanisms are present. A transient-transfection approach was employed to show that p27 can inhibit Ras activation by targeting GRB2 and further revealed that the CDK and GRB2 inhibitory functions of p27 are separable and distinct. Thus, p27 downregulation may compromise control of Ras, one of the most common oncogenic events in human cancer.

* Corresponding author. Mailing address: University of Minnesota Cancer Center, MMC 806, 420 Delaware St. SE, Minneapolis, MN 55455. Phone: (612) 626-4778. Fax: (612) 626-3941. E-mail: sheaf004{at}tc.umn.edu.

{dagger} Present address: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309.

Molecular and Cellular Biology, June 2003, p. 3735-3752, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.3735-3752.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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