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J. Biol. Chem., Vol. 279, Issue 3, 1956-1967, January 16, 2004

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Jak2 Tyrosine Kinase Mediates Angiotensin II-dependent Inactivation of ERK2 via Induction of Mitogen-activated Protein Kinase Phosphatase 1^*

Eric M. Sandberg, Xianyue Ma, Dannielle VonDerLinden, Michael D. Godeny, and Peter P. Sayeski

From the Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida 32610

Previous work has shown that inhibition of Jak2 via the pharmacological compound AG490 blocks the angiotensin II (Ang II)-dependent activation of ERK2, thereby suggesting an essential role of Jak2 in ERK activation. However, recent studies have thrown into question the specificity of AG490 and therefore the role of Jak2 in ERK activation. To address this, we reconstituted an Ang II signaling system in a Jak2–/–cell line and measured the ability of Ang II to activate ERK2 in these cells. Controls for this study were the same cells expressing Jak2 via the addition of a Jak2 expression plasmid. In the cells expressing Jak2, Ang II induced a marked increase in ERK2 activity as measured by Western blot analysis and in vitro kinase assays. ERK2 activity returned to basal levels within 30 min. However, in the cells lacking Jak2, Ang II treatment resulted in ERK2 activation that did not return to basal levels until 120 min after ligand addition. Analysis of phosphatase gene expression revealed that Ang II induced mitogen-activated protein kinase phosphatase 1 (MKP-1) expression in cells expressing Jak2 but failed to induce MKP-1 expression in cells lacking Jak2. Therefore, our results suggest that Jak2 is not required for Ang II-induced ERK2 activation. Rather Jak2 is required for Ang II-induced ERK2 inactivation via induction of MKP-1 gene expression.

Received for publication, April 4, 2003 , and in revised form, October 2, 2003.

^* This work was supported by a Biomedical Research Support Program for Medical Schools award to the University of Florida College of Medicine by the Howard Hughes Medical Institute, American Heart Association National Scientist Development Grant 0130041N, and National Institutes of Health Awards K01-DK60471 and R01-HL67277. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a University of Florida Medical Guild fellowship and a predoctoral fellowship from the Florida/Puerto Rico affiliate of the American Heart Association.

To whom correspondence should be addressed: Dept. of Physiology and Functional Genomics, P. O. Box 100274, University of Florida College of Medicine, Gainesville, FL 32610. Tel.: 352-392-1816; Fax: 352-846-0270; E-mail: psayeski{at}phys.med.ufl.edu.

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