Article
- The EMBO Journal (2005) 24, 3869 - 3880
- doi:10.1038/sj.emboj.7600856
Published online: 27 October 2005
Subject Categories:
Critical role of novel Thr-219 autophosphorylation for the cellular function of PKC
in T lymphocytes
Nikolaus Thuille1,a, Isabelle Heit2,a, Friedrich Fresser1, Nina Krumböck1, Birgit Bauer1, Sabine Leuthaeusser2, Sascha Dammeier2, Caroline Graham3, Terry D Copeland3, Steve Shaw3 and Gottfried Baier1
- Department for Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Innsbruck, Austria
- ALTANA Pharma AG, Konstanz, Germany
- Experimental Immunology Branch, National Cancer Institute, Bethesda, MD, USA
Correspondence to:
Gottfried Baier,
Section for Human Genetics, Innsbruck Medical University, Schoepfstra
e 41, 6020 Innsbruck, Austria. Tel.: +43 512 507 3451; Fax: +43 512 507 2861; E-mail: gottfried.baier@uibk.ac.at
aThese authors contributed equally to this work
Received 19 May 2005; Accepted 7 October 2005
Abstract
Phosphopeptide mapping identified a major autophosphorylation site, phospho (p)Thr-219, between the tandem C1 domains of the regulatory fragment in protein kinase C (PKC)
. Confirmation of this identification was derived using (p)Thr-219 antisera that reacted with endogenous PKC in primary CD3+ T cells after stimulation with phorbol ester, anti-CD3 or vanadate. The T219A mutation abrogated the capacity of PKC to mediate NF-
B, NF-AT and interleukin-2 promoter transactivation, and reduced PKC's ability in Jurkat T cells to phosphorylate endogenous cellular substrates. In particular, the T219A mutation impaired crosstalk of PKC with Akt/PKB
in NF-B activation. Yet, this novel (p)Thr-219 site did not affect catalytic activity or second-messenger lipid-binding activity in vitro. Instead, the T219A mutation prevented proper recruitment of PKC in activated T cells. The PKCT219A mutant defects were largely rescued by addition of a myristoylation signal to force its proper membrane localization. We conclude that autophosphorylation of PKC at Thr-219 plays an important role in the correct targeting and cellular function of PKC upon antigen receptor ligation.
Keywords:
- autophosphorylation,
- cellular function,
- IL-2 activation,
- PKC,
- T cells
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