title: CISK attenuates degradation of the chemokine receptor CXCR4 via the ubiquitin ligase AIP4.
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.
authors.affiliation: Department of Biochemistry, The Norwegian Radium Hospital and the University of Oslo, Montebello, Oslo, Norway.
authors.forename: Thomas
authors.initials: T
authors.lastname: Slagsvold
authors.forename: Adriano
authors.initials: A
authors.lastname: Marchese
authors.forename: Andreas
authors.initials: A
authors.lastname: Brech
authors.forename: Harald
authors.initials: H
authors.lastname: Stenmark
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000595:Amino Acid Sequence; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D019718:Receptors, CXCR4; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C432966:ITCH protein, human; C578562:PDPK1 protein, human