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CISK attenuates degradation of the chemokine receptor CXCR4 via the ubiquitin ligase AIP4. EMBO J 2006 Aug 23;25(16):3738-49

Date

08/05/2006

Pubmed ID

16888620

Pubmed Central ID

PMC1553197

DOI

10.1038/sj.emboj.7601267

Scopus ID

2-s2.0-33748041667   55 Citations

Abstract

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.

Author List

Slagsvold T, Marchese A, Brech A, Stenmark H

Author

Adriano Marchese PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

3-Phosphoinositide-Dependent Protein Kinases
Amino Acid Sequence
Endosomes
Enzyme Activation
HeLa Cells
Humans
Immediate-Early Proteins
Lysosomes
Molecular Sequence Data
Phosphorylation
Protein Transport
Protein-Serine-Threonine Kinases
Proteinase Inhibitory Proteins, Secretory
Proteins
Receptors, CXCR4
Repressor Proteins
Signal Transduction
Ubiquitin-Protein Ligases