Article
- The EMBO Journal (2007) 26, 4619 - 4633
- doi:10.1038/sj.emboj.7601891
Published online: 25 October 2007
Subject Category:
Phosphorylation at Ser244 by CK1 determines nuclear localization and substrate targeting of PKD2
J von Blume1,a, Uwe Knippschild2, Franck Dequiedt3, Georgios Giamas2, Alexander Beck4, Alexandra Auer1, Johan Van Lint5, Guido Adler1 and Thomas Seufferlein1
- Department of Internal Medicine I, University of Ulm, Ulm, Germany
- Department of Surgery 1, University of Ulm, Ulm, Germany
- Laboratory of Molecular and Cellular Biology, FUSAGx, Gembloux, Belgium
- PANATecs, Tübingen, Germany
- Department of Molecular Cell Biology, Molecular Medicine of Protein Kinases, KU Leuven, Belgium
Correspondence to:
Thomas Seufferlein, Department of Internal Medicine I, University of Ulm, Robert Koch Strasse 8, Ulm 89081, Germany. Tel.: +49 731 50024308; Fax: +49 731 50024302; E-mail: thomas.seufferlein@uniklinik-ulm.de
aPresent address: Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA
Received 20 April 2007; Accepted 18 September 2007
Abstract
Protein kinase D2 (PKD2), a member of the PKD family of serine/threonine kinases, is localized in various subcellular compartments including the nucleus where the kinase accumulates upon activation of G-protein-coupled receptors. We define three critical post-translational modifications required for nuclear accumulation of PKD2 in response to activation of the CCK2 receptor (CCK2R): phosphorylation at Ser706 and Ser710 within the activation loop by PKC
leading to catalytic activity and phosphorylation at Ser244 within the zinc-finger domain, which is crucial for blocking nuclear export of active PKD2 by preventing its interaction with the Crm-1 export machinery. We identify CK1
and 
as upstream activated kinases by CCK2R that phosphorylate PKD2 at Ser244. Moreover, nuclear accumulation of active PKD2 is a prerequisite for efficient phosphorylation of its nuclear substrate, HDAC7. Only nuclear, active PKD2 mediates CCK2R-induced HDAC7 phosphorylation and Nur77 expression. Thus, we define a novel, compartment-specific signal transduction pathway downstream of CCK2R that phosphorylates PKD2 at three specific sites, results in nuclear accumulation of the active kinase and culminates in efficient phosphorylation of nuclear PKD2 substrates in human gastric cancer cells.
Keywords:
- CK1,
- compartment-specific signalling,
- gastric cancer,
- HDACs,
- PKD2
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