title: Hsc/Hsp70 interacting protein (hip) associates with CXCR2 and regulates the receptor signaling and trafficking.
abstract: The ligand-induced trafficking of chemokine receptors plays a significant role in the regulation of inflammatory processes and human immunodeficiency infection. Although many chemokine receptors have been demonstrated to internalize through clathrin-coated vesicles, a process that involves the binding of arrestins to the receptors, accumulating evidence has suggested the possible existence of other regulators. In a yeast two-hybrid screening using the C-terminal domain of CXCR2 as a bait, the Hsc70-interacting protein (Hip) was identified to interact with CXCR2. Hip binds CXCR2 through its C-terminal domain binding to the C-terminal leucine-rich domain (KILAIHGLI) of CXCR2. Hip associates with CXCR2 or CXCR4 in intact cells, and agonist stimulation increases the association. Mutation of the Ile-Leu motif in the C-terminal domain of CXCR2 blocks the agonist-dependent association of the mutant receptor with Hip. Overexpression of a tetratricopeptide repeat (TPR) deletion mutant form of Hip (Delta TPR), which is unable to bind Hsc70 (Prapapanich, V., Chen, S., Nair, S. C., Rimerman, R. A., and Smith, D. F. (1996) Mol. Endocrinol. 10, 420-431), but retains the ability to bind CXCR2, does not affect CXCR2-mediated mitogen-activated protein kinase activation. However, overexpression of Delta TPR significantly attenuates the agonist-induced internalization of CXCR2 and CXCR4 and attenuates CXCR2-mediated chemotaxis. These findings open the possibility for regulation of chemokine receptor signaling and trafficking by protein chaperone molecules.
authors.affiliation: Department of Veterans Affairs, Nashville, Tennessee 37212-2637, USA.
authors.forename: Guo-Huang
authors.initials: GH
authors.lastname: Fan
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Jiqing
authors.initials: J
authors.lastname: Sai
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
mesh_terms: D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D015723:Gene Library; D006801:Humans; D007700:Kinetics; D015471:Leukemia, Basophilic, Acute; D008024:Ligands; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D019718:Receptors, CXCR4 / Q000502:physiology; D023063:Receptors, Interleukin-8B / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D018832:Molecular Chaperones
chemical_list: D002352:Carrier Proteins; D008024:Ligands; D010446:Peptide Fragments; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; C101119:ST13 protein, human; D018832:Molecular Chaperones