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Molecular and Cellular Biology, February 2004, p. 1582-1594, Vol. 24, No. 4
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.4.1582-1594.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Negative Control of the Myc Protein by the Stress-Responsive Kinase Pak2

Zhongdong Huang,1* Jolinda A. Traugh,2 and J. Michael Bishop1

The George Williams Hooper Foundation, University of California, San Francisco, California 94143-0552,1 Department of Biochemistry, University of California, Riverside, California 925212

Received 11 September 2003/ Returned for modification 8 October 2003/ Accepted 11 November 2003

Pak2 is a serine/threonine kinase that participates in the cellular response to stress. Among the potential substrates for Pak2 is the protein Myc, encoded by the proto-oncogene MYC. Here we demonstrate that Pak2 phosphorylates Myc at three sites (T358, S373, and T400) and affects Myc functions both in vitro and in vivo. Phosphorylation at all three residues reduces the binding of Myc to DNA, either by blocking the requisite dimerization with Max (through phosphorylation at S373 and T400) or by interfering directly with binding to DNA (through phosphorylation at T358). Phosphorylation by Pak2 inhibits the ability of Myc to activate transcription, to sustain cellular proliferation, to transform NIH 3T3 cells in culture, and to elicit apoptosis on serum withdrawal. These results indicate that Pak2 is a negative regulator of Myc, suggest that inhibition of Myc plays a role in the cellular response to stress, and raise the possibility that Pak2 may be the product of a tumor suppressor gene.

* Corresponding author. Mailing address: The George Williams Hooper Foundation, Box 0552, University of California San Francisco, San Francisco, CA 94143-0552. Phone: (415) 476-5350. Fax: (415) 476-6185. E-mail: huangzd{at}itsa.ucsf.edu.

Molecular and Cellular Biology, February 2004, p. 1582-1594, Vol. 24, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.4.1582-1594.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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