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Molecular and Cellular Biology, June 2006, p. 4052-4062, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01591-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Phosphorylation of JAK2 at Serine 523: a Negative Regulator of JAK2 That Is Stimulated by Growth Hormone and Epidermal Growth Factor

Anna M. Mazurkiewicz-Munoz,1,{dagger} Lawrence S. Argetsinger,2,{dagger} Jean-Louis K. Kouadio,2 Allan Stensballe,3 Ole N. Jensen,3 Joel M. Cline,2 and Christin Carter-Su2*

Graduate Program in Cellular and Molecular Biology,1 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622,2 Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark3

Received 17 August 2005/ Returned for modification 20 September 2005/ Accepted 8 March 2006

The tyrosine kinase JAK2 is a key signaling protein for at least 20 receptors in the cytokine/hematopoietin receptor superfamily and is a component of signaling for multiple receptor tyrosine kinases and several G-protein-coupled receptors. In this study, phosphopeptide affinity enrichment and mass spectrometry identified serine 523 (Ser523) in JAK2 as a site of phosphorylation. A phosphoserine 523 antibody revealed that Ser523 is rapidly but transiently phosphorylated in response to growth hormone (GH). MEK1 inhibitor UO126 suppresses GH-dependent phosphorylation of Ser523, suggesting that extracellular signal-regulated kinases (ERKs) 1 and/or 2 or another kinase downstream of MEK1 phosphorylate Ser523 in response to GH. Other ERK activators, phorbol 12-myristate 13-acetate and epidermal growth factor, also stimulate phosphorylation of Ser523. When Ser523 in JAK2 was mutated, JAK2 kinase activity as well as GH-dependent tyrosyl phosphorylation of JAK2 and Stat5 was enhanced, suggesting that phosphorylation of Ser523 inhibits JAK2 kinase activity. We hypothesize that phosphorylation of Ser523 in JAK2 by ERKs 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner to dampen activation of JAK2 in response to GH and provides a mechanism by which prior exposure to environmental factors that regulate Ser523 phosphorylation might modulate the cell's response to GH.

* Corresponding author. Mailing address: Department of Molecular and Integrative Physiology, The University of Michigan Medical School, Ann Arbor, MI 48109-0622. Phone: (734) 763-2561. Fax: (734) 647-9523. E-mail: cartersu{at}umich.edu.

{dagger} These two authors contributed equally to this work.

Molecular and Cellular Biology, June 2006, p. 4052-4062, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01591-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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