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J. Biol. Chem., Vol. 282, Issue 7, 4573-4584, February 16, 2007

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Modulation of DRAK2 Autophosphorylation by Antigen Receptor Signaling in Primary Lymphocytes^*

Monica L. Friedrich¹, Meng Cui, Jeniffer B. Hernandez, Brian M. Weist, Hilde-Marie Andersen, Xiaowu Zhang^¶, Lan Huang^||2, and Craig M. Walsh^||3

From the Center for Immunology and Department of Molecular Biology & Biochemistry, Departments of Physiology & Biophysics and Developmental & Cell Biology, ^||Cancer Research Institute, University of California, Irvine, Irvine, California 92697 and ^¶Cell Signaling Technology, Inc., Danvers, Massachusetts 01923

Death-associated protein-related apoptotic kinase-2 (DRAK2), a member of the death-associated protein-like family of serine/threonine kinases, is highly expressed in lymphoid organs and is a negative regulator of T cell activation. To investigate the regulation of DRAK2 activity in primary lymphocytes, we employed mass spectrometry to identify sites of autophosphorylation on DRAK2. These studies have revealed a key site of autophosphorylation on serine 12. Using a phospho-specific antibody to detect Ser¹² phosphorylation, we found that autophosphorylation is induced by antigen receptor stimulation in T and B cells. In Jurkat T cells, resting B cells and thymocytes, DRAK2 was hypophosphorylated on Ser¹² but rapidly phosphorylated with antigen receptor ligation. This increase in phosphorylation was dependent on intracellular calcium mobilization, because BAPTA-AM blocked DRAK2 kinase activity, whereas the SERCA inhibitor thapsigargin promoted Ser¹² phosphorylation. Our results show that DRAK2 kinase activity is regulated in a calcium-dependent manner and that Ser¹² phosphorylation is necessary for optimal suppression of T cell activation by this kinase, suggesting a potential feedback loop may act to modulate the activity of this kinase following antigen receptor signaling.

Received for publication, July 13, 2006 , and in revised form, November 30, 2006.

^* The work was supported in part by research grants from the Arthritis National Research Foundation (to C. M. W.), by National Institutes of Health (NIH) Grant AI063419 (to C. M. W.) and GM074830 (to L. H.), and by Department of the Army Grant PC-041126 (to L. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Supported by pre-doctoral Training Grant T32GM007311 from NIH.

² To whom correspondence may be addressed: D224 Medical Sciences I, University of California, Irvine, Irvine CA 92697-4560. Tel.: 949-824-8548; Fax: 949-824-8540; E-mail: lanhuang{at}uci.edu. ³ To whom correspondence may be addressed: University of California, 3215 McGaugh Hall, Irvine, Irvine, CA 92697-3900. Tel.: 949-824-8487; Fax: 949-824-8551; E-mail: cwalsh{at}uci.edu.

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