title: Intracellular cross-talk between the GPCR CXCR1 and CXCR2: role of carboxyl terminus phosphorylation sites.
abstract: In the present study, we used the human chemokine receptors CXCR1 and CXCR2 as a model system for the study of intracellular cross-talk between two closely related G protein-coupled receptors (GPCR). In cells expressing either CXCR1 or CXCR2, exposure to the CXCL8 ligand resulted in prominent reduction in cell surface expression of the receptors. We have shown previously that the reduction in cell surface expression of CXCR1 and CXCR2, to be termed herein "down-regulation", is significantly lower in cells expressing both receptors together. Now we show that reduced receptor down-regulation was specific to the CXCR1+CXCR2 pair. Also, CXCR2 carboxyl terminus phosphorylation sites were required for inducing inhibition of CXCR1 down-regulation, and vice versa. Accordingly, phosphorylation of CXCR2 carboxyl terminus domain was intact when expressed together with CXCR1. Moreover, specific carboxyl terminus phosphorylation sites on each of the wild type receptors protected them from more severe inhibition of down-regulation, induced by joint expression with the other receptor. When concomitantly expressed, CXCR1 and CXCR2 were impaired in recycling to the plasma membrane, despite their undergoing intact dephosphorylation. Overall, we show that cross-talk between two GPCR is manifested by impairment of their intracellular trafficking, primarily of ligand-induced down-regulation, via carboxyl terminus phosphorylation sites.
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Attal
authors.forename: Efrat
authors.initials: E
authors.lastname: Cohen-Hillel
authors.forename: Tsipi
authors.initials: T
authors.lastname: Meshel
authors.forename: Ji Ming
authors.initials: JM
authors.lastname: Wang
authors.forename: Wanghua
authors.initials: W
authors.lastname: Gong
authors.forename: Adit
authors.initials: A
authors.lastname: Ben-Baruch
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D023062:Receptors, Interleukin-8A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D043562:Receptors, G-Protein-Coupled; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B