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Molecular and Cellular Biology, June 2003, p. 3813-3824, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.3813-3824.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Inactivation of Dual-Specificity Phosphatases Is Involved in the Regulation of Extracellular Signal-Regulated Kinases by Heat Shock and Hsp72

Julia Yaglom, Cornelia O'Callaghan-Sunol, Vladimir Gabai, and Michael Y. Sherman*

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

Received 1 August 2002/ Returned for modification 29 October 2002/ Accepted 3 March 2003

Extracellular signal-regulated kinase 1 (ERK1) and ERK2 (ERK1/2) dramatically enhance survival of cells exposed to heat shock. Using Cos-7 cells and primary human fibroblasts (IMR90 cells), we demonstrated that heat shock activates ERKs via two distinct mechanisms: stimulation of the ERK-activating kinases, MEK1/2, and inhibition of ERK dephosphorylation. Under milder heat shock conditions, activation of ERKs proceeded mainly through stimulation of MEK1/2, whereas under more severe heat shock MEK1/2 could no longer be activated and the inhibition of ERK phosphatases became critical. In Cos-7 cells, nontoxic heat shock caused rapid inactivation of the major ERK phosphatase, MKP-3, by promoting its aggregation, so that in cells exposed to 45°C for 20 min, 90% of MKP-3 became insoluble. MKP-3 aggregation was reversible and, 1 h after heat shock, MKP-3 partially resolubilized. The redistribution of MKP-3 correlated with an increased rate of ERK dephosphorylation. Similar heat-induced aggregation, followed by partial resolubilization, was found with a distinct dual-specificity phosphatase MKP-1 but not with MKP-2. Therefore, MKP-3 and MKP-1 appeared to be critical heat-labile phosphatases involved in the activation of ERKs by heat shock. Expression of the major heat shock protein Hsp72 inhibited activation of MEK1/2 and prevented inactivation of MKP-3 and MKP-1. Hsp72{Delta}EEVD mutant lacking a chaperone activity was unable to protect MKP-3 from heat inactivation but interfered with MEK1/2 activation similar to normal Hsp72. Hence, Hsp72 suppressed ERK activation by both protecting dual-specificity phosphatases, which was dependent on the chaperone activity, and suppressing MEK1/2, which was independent of the chaperone activity.

* Corresponding author. Mailing address: Boston University School of Medicine, Department of Biochemistry, K323, 715 Albany St., Boston, MA 02118. Phone: (617) 638-5971. Fax: (617) 638-5339. E-mail: sherman{at}biochem.bumc.bu.edu.

Molecular and Cellular Biology, June 2003, p. 3813-3824, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.3813-3824.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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