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Molecular and Cellular Biology, September 2000, p. 6984-6995, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

p50Cdc37 Can Buffer the Temperature-Sensitive Properties of a Mutant of Hck

Glen Scholz,1,* Steven D. Hartson,2 Kellie Cartledge,1 Nathan Hall,3,4 Jieya Shao,2 Ashley R. Dunn,1 and Robert L. Matts2

Molecular Biology Laboratory1 and Molecular Modelling Laboratory,3 Ludwig Institute for Cancer Research, Royal Melbourne Hospital, and The Cooperative Research Centre for Cellular Growth Factors,4 Victoria 3050, Australia, and Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, Oklahoma 740782

Received 30 March 2000/Returned for modification 22 May 2000/Accepted 27 June 2000

Genetic studies have previously revealed that Cdc37p is required for the catalytic competence of v-Src in yeast. We have reasoned that temperature-sensitive mutants of Src family kinases might be more sensitive to the cellular level of p50Cdc37, the mammalian homolog of Cdc37p, than their wild-type counterpart, thus potentially providing a unique opportunity to elucidate the involvement of p50Cdc37 in the folding and stabilization of Src family kinases. A temperature-sensitive mutant of a constitutively active form of Hck (i.e., tsHck499F) was created by mutating two amino acids within the kinase domain of Hck499F. Significantly, overexpression of p50Cdc37 rescues the catalytic activity of tsHck499F at 33°C, while partially buffering it against inactivation at higher temperatures (e.g., 37 and 39°C). Hsp90 function is required for tsHck499F activity and its stabilization by p50Cdc37, but overexpression of Hsp90 is not sufficient to stabilize tsHck499F. Overexpression of p50Cdc37 promotes the association of tsHck499F with Hsp90, suggesting that the cellular level of p50Cdc37 might be the rate-limiting step in the association of tsHck499F with Hsp90. A truncation mutant of p50Cdc37 that cannot bind Hsp90 still has a limited capacity to rescue the catalytic activity of tsHck499F and promote its association with Hsp90. This is a particularly important observation, since it argues that rather than solely acting as a passive adapter protein to tether tsHck499F to Hsp90, p50Cdc37 may also act allosterically to enhance the association of tsHck499F with Hsp90. The findings presented here might also have implications for our understanding of the evolution of protein kinases and tumor development.

* Corresponding author. Mailing address: Molecular Biology Laboratory, Ludwig Institute for Cancer Research, P.O. Box 2008, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. Phone: 61-3-9341 3155. Fax: 61-3-9341 3191. E-mail: Glen.Scholz{at}ludwig.edu.au.

Molecular and Cellular Biology, September 2000, p. 6984-6995, Vol. 20, No. 18
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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