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Molecular and Cellular Biology, October 2003, p. 7377-7390, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7377-7390.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The COOH-Terminal Domain of Wild-Type Cot Regulates Its Stability and Kinase Specific Activity

Maria Luisa Gándara, Pilar López, Raquel Hernando, José G. Castaño, and Susana Alemany*

Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Facultad Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain

Received 2 May 2003/ Returned for modification 17 June 2003/ Accepted 15 July 2003

Cot, initially identified as an oncogene in a truncated form, is a mitogen-activated protein kinase kinase kinase implicated in cellular activation and proliferation. Here, we show that this truncation of Cot results in a 10-fold increase in its overall kinase activity through two different mechanisms. Truncated Cot protein exhibits a lower turnover rate (half-life, 95 min) than wild-type Cot (half-life, 35 min). The degradation of wild-type and truncated Cot can be specifically inhibited by proteasome inhibitors in situ. The 20S proteasome also degrades wild-type Cot more efficiently than the truncated protein. Furthermore, the amino acid 435 to 457 region within the wild-type Cot COOH-terminal domain confers instability when transferred to the yellow fluorescent protein and targets this fusion protein to degradation via the proteasome. On the other hand, the kinase specific activity of wild-type Cot is 3.8-fold lower than that of truncated Cot, and it appears that the last 43 amino acids of the wild-type Cot COOH-terminal domain are those responsible for this inhibition of kinase activity. In conclusion, these data demonstrate that the oncogenic activity of truncated Cot is the result of its prolonged half-life and its higher kinase specific activity with respect to wild-type Cot.

* Corresponding author. Mailing address: Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain. Phone: 34-91-3975418. Fax: 34-91-5854401. E-mail: salemany{at}iib.uam.es.

Molecular and Cellular Biology, October 2003, p. 7377-7390, Vol. 23, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.20.7377-7390.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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