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Article

  • The EMBO Journal (2006) 25, 3738 - 3749
  • doi:10.1038/sj.emboj.7601267

Published online: 3 August 2006

CISK attenuates degradation of the chemokine receptor CXCR4 via the ubiquitin ligase AIP4

Thomas Slagsvold1, Adriano Marchese2, Andreas Brech1 and Harald Stenmark1

  1. Department of Biochemistry, The Norwegian Radium Hospital and the University of Oslo, Montebello, Oslo, Norway
  2. Department of Pharmacology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA

Correspondence to:

Adriano Marchese, Department of Pharmacology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA. Tel.: +1 708 216 3456; Fax: +1 708 216 6596; E-mail: amarchese@lumc.edu

Harald Stenmark, Department of Biochemistry, The Norwegian Radium Hospital and The University of Oslo, Montebello, Oslo 0310, Norway. Tel.: +47 2293 4951; Fax: +47 2250 8692; E-mail: stenmark@ulrik.uio.no

Received 4 November 2005; Accepted 12 July 2006

HER2 overexpression in cancers causes hyperactivation of the PI 3-kinase pathway and elevated levels of the chemokine receptor CXCR4, which is strongly associated with increased metastatic potential. Here, we provide evidence that the cytokine-independent survival kinase CISK is activated downstream of the PI 3-kinase-dependent kinase PDK1 on endosomes and negatively regulates the lysosomal degradation of CXCR4. We demonstrate that CISK prevents CXCR4 degradation by inhibiting sorting of the receptor from early endosomes to lysosomes. In contrast, CISK does not interfere with ligand-induced degradation of epidermal growth factor receptors. CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro. Taken together, these results reveal a critical function of CISK in specifically attenuating ubiquitin-dependent degradation of CXCR4, and provide a mechanistic link between the PI 3-kinase pathway and CXCR4 stability.

  • Keywords:

    • chemokine receptor,
    • endocytosis,
    • lysosome,
    • PI 3-kinase,
    • ubiquitin