| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037;
Department of Medicine, University of California, San Diego, CA 92093; and
La Jolla Institute of Experimental Medicine, La Jolla, CA 92037
The chemokine receptor CXCR2 is the closest homologue to Kaposi’s sarcoma herpesvirus-G protein-coupled receptor (KSHV-GPCR), which is known to be constitutively activated and able to cause oncogenic transformation. Among G protein-coupled receptors, a DRY sequence in the second intracellular loop is highly conserved. However, the KSHV-GPCR shows a VRY sequence instead. In this study, we exchanged Asp138 of the DRY sequence in the CXCR2 with a Val (D138V), the corresponding amino acid in KSHV-GPCR, or with a Gln (D138Q), and investigated the functional consequences of these mutations. In focus formation and soft agar growth assays in NIH 3T3 cells, the D138V mutant exhibited transforming potential similar to the KSHV-GPCR. Surprisingly, the CXCR2 wild type itself showed transforming activity, although not as potently, due to continuous autocrine stimulation, whereas the D138Q mutant formed no foci. In agreement with these results were high levels of inositol phosphate accumulation in the D138V mutant and the KSHV-GPCR, indicating constitutive activity. These data emphasize the importance of the DRY sequence for G protein-coupled signaling of the CXCR2. Either constitutive activation or persistent autocrine stimulation of the CXCR2 causes transformation similar to KSHV-GPCR-transfected cells, probably activating the same signal transduction cascade that can abrogate normal growth control mechanisms.
This article has been cited by other articles:
|
|
 |
|
  Y. Yu, Y. Su, S. R. Opalenik, T. Sobolik-Delmaire, N. F. Neel, S. Zaja-Milatovic, S. T. Short, J. Sai, and A. Richmond Short tail with skin lesion phenotype occurs in transgenic mice with keratin-14 promoter-directed expression of mutant CXCR2 J. Leukoc. Biol., August 1, 2008; 84(2): 406 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Verzijl, S. Storelli, D. J. Scholten, L. Bosch, T. A. Reinhart, D. N. Streblow, C. P. Tensen, C. P. Fitzsimons, G. J. R. Zaman, J. E. Pease, et al. Noncompetitive Antagonism and Inverse Agonism as Mechanism of Action of Nonpeptidergic Antagonists at Primate and Rodent CXCR3 Chemokine Receptors J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 544 - 555. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Case, E. Sharp, T. Benned-Jensen, M. M. Rosenkilde, N. Davis-Poynter, and H. E. Farrell Functional Analysis of the Murine Cytomegalovirus Chemokine Receptor Homologue M33: Ablation of Constitutive Signaling Is Associated with an Attenuated Phenotype In Vivo J. Virol., February 15, 2008; 82(4): 1884 - 1898. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Maussang, D. Verzijl, M. van Walsum, R. Leurs, J. Holl, O. Pleskoff, D. Michel, G. A. M. S. van Dongen, and M. J. Smit Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis PNAS, August 29, 2006; 103(35): 13068 - 13073. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ueda, N. F. Neel, E. Schutyser, D. Raman, and A. Richmond Deletion of the COOH-Terminal Domain of CXC Chemokine Receptor 4 Leads to the Down-regulation of Cell-to-Cell Contact, Enhanced Motility and Proliferation in Breast Carcinoma Cells Cancer Res., June 1, 2006; 66(11): 5665 - 5675. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Najarro, C. Gubser, M. Hollinshead, J. Fox, J. Pease, and G. L. Smith Yaba-like disease virus chemokine receptor 7L, a CCR8 orthologue. J. Gen. Virol., April 1, 2006; 87(Pt 4): 809 - 816. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Rosenkilde, T. N. Kledal, and T. W. Schwartz High Constitutive Activity of a Virus-Encoded Seven Transmembrane Receptor in the Absence of the Conserved DRY Motif (Asp-Arg-Tyr) in Transmembrane Helix 3 Mol. Pharmacol., July 1, 2005; 68(1): 11 - 19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Lagane, S. Ballet, T. Planchenault, K. Balabanian, E. Le Poul, C. Blanpain, Y. Percherancier, I. Staropoli, G. Vassart, M. Oppermann, et al. Mutation of the DRY Motif Reveals Different Structural Requirements for the CC Chemokine Receptor 5-Mediated Signaling and Receptor Endocytosis Mol. Pharmacol., June 1, 2005; 67(6): 1966 - 1976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. K. Gruijthuijsen, E. V. H. Beuken, M. J. Smit, R. Leurs, C. A. Bruggeman, and C. Vink Mutational analysis of the R33-encoded G protein-coupled receptor of rat cytomegalovirus: identification of amino acid residues critical for cellular localization and ligand-independent signalling J. Gen. Virol., April 1, 2004; 85(4): 897 - 909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Liu, G. Sandford, G. Fei, and J. Nicholas G{alpha} Protein Selectivity Determinant Specified by a Viral Chemokine Receptor-Conserved Region in the C Tail of the Human Herpesvirus 8 G Protein-Coupled Receptor J. Virol., March 1, 2004; 78(5): 2460 - 2471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Dadke, B. H. Fryer, E. A. Golemis, and J. Field Activation of p21-Activated Kinase 1-Nuclear Factor {kappa}B Signaling by Kaposi's Sarcoma-Associated Herpes Virus G Protein-Coupled Receptor during Cellular Transformation Cancer Res., December 15, 2003; 63(24): 8837 - 8847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. U. Schraufstatter, K. Trieu, M. Zhao, D. M. Rose, R. A. Terkeltaub, and M. Burger IL-8-Mediated Cell Migration in Endothelial Cells Depends on Cathepsin B Activity and Transactivation of the Epidermal Growth Factor Receptor J. Immunol., December 15, 2003; 171(12): 6714 - 6722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Mukaida Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases Am J Physiol Lung Cell Mol Physiol, April 1, 2003; 284(4): L566 - L577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Estep, M. K. Axthelm, and S. W. Wong A G Protein-Coupled Receptor Encoded by Rhesus Rhadinovirus Is Similar to ORF74 of Kaposi's Sarcoma-Associated Herpesvirus J. Virol., February 1, 2003; 77(3): 1738 - 1746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cannon, N. J. Philpott, and E. Cesarman The Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Has Broad Signaling Effects in Primary Effusion Lymphoma Cells J. Virol., December 6, 2002; 77(1): 57 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Dhawan and A. Richmond Role of CXCL1 in tumorigenesis of melanoma J. Leukoc. Biol., July 1, 2002; 72(1): 9 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-J. Chiou, L. J. Poole, P. S. Kim, D. M. Ciufo, J. S. Cannon, C. M. ap Rhys, D. J. Alcendor, J.-C. Zong, R. F. Ambinder, and G. S. Hayward Patterns of Gene Expression and a Transactivation Function Exhibited by the vGCR (ORF74) Chemokine Receptor Protein of Kaposi's Sarcoma-Associated Herpesvirus J. Virol., March 7, 2002; 76(7): 3421 - 3439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Smit, D. Verzijl, P. Casarosa, M. Navis, H. Timmerman, and R. Leurs Kaposi's Sarcoma-Associated Herpesvirus-Encoded G Protein-Coupled Receptor ORF74 Constitutively Activates p44/p42 MAPK and Akt via Gi and Phospholipase C-Dependent Signaling Pathways J. Virol., February 15, 2002; 76(4): 1744 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Ye Regulation of nuclear factor {kappa}B activation by G-protein-coupled receptors J. Leukoc. Biol., December 1, 2001; 70(6): 839 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. W. Shepard, M. Yang, P. Xie, D. D. Browning, T. Voyno-Yasenetskaya, T. Kozasa, and R. D. Ye Constitutive Activation of NF-kappa B and Secretion of Interleukin-8 Induced by the G Protein-coupled Receptor of Kaposi's Sarcoma-associated Herpesvirus Involve Galpha 13 and RhoA J. Biol. Chem., November 30, 2001; 276(49): 45979 - 45987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Pati, M. Cavrois, H.-G. Guo, J. S. Foulke Jr., J. Kim, R. A. Feldman, and M. Reitz Activation of NF-{kappa}B by the Human Herpesvirus 8 Chemokine Receptor ORF74: Evidence for a Paracrine Model of Kaposi's Sarcoma Pathogenesis J. Virol., September 15, 2001; 75(18): 8660 - 8673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schwarz and P. M. Murphy Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Constitutively Activates NF-{{kappa}}B and Induces Proinflammatory Cytokine and Chemokine Production Via a C-Terminal Signaling Determinant J. Immunol., July 1, 2001; 167(1): 505 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. U. Schraufstatter, J. Chung, and M. Burger IL-8 activates endothelial cell CXCR1 and CXCR2 through Rho and Rac signaling pathways Am J Physiol Lung Cell Mol Physiol, June 1, 2001; 280(6): L1094 - L1103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N. Wakeling, D. J. Roy, A. A. Nash, and J. P. Stewart Characterization of the murine gammaherpesvirus 68 ORF74 product: a novel oncogenic G protein-coupled receptor J. Gen. Virol., May 1, 2001; 82(5): 1187 - 1197. [Abstract] [Full Text]
|
|
|
|
|
|
S. Montaner, A. Sodhi, S. Pece, E. A. Mesri, and J. S. Gutkind The Kaposi's Sarcoma-associated Herpesvirus G Protein-coupled Receptor Promotes Endothelial Cell Survival through the Activation of Akt/Protein Kinase B Cancer Res., March 1, 2001; 61(6): 2641 - 2648. [Abstract] [Full Text]
|
|
|
|
|
|
A. Sodhi, S. Montaner, V. Patel, M. Zohar, C. Bais, E. A. Mesri, and J. S. Gutkind The Kaposi's Sarcoma-associated Herpes Virus G Protein-coupled Receptor Up-Regulates Vascular Endothelial Growth Factor Expression and Secretion through Mitogen-activated Protein Kinase and p38 Pathways Acting on Hypoxia-inducible Factor 1{{alpha}} Cancer Res., September 1, 2000; 60(17): 4873 - 4880. [Abstract] [Full Text]
|
|
|
|
|
|
J. A. Belperio, M. P. Keane, D. A. Arenberg, C. L. Addison, J. E. Ehlert, M. D. Burdick, and R. M. Strieter CXC chemokines in angiogenesis J. Leukoc. Biol., July 1, 2000; 68(1): 1 - 8. [Abstract] [Full Text]
|
|
|
|
|
|
M. M. Rosenkilde, T. N. Kledal, P. J. Holst, and T. W. Schwartz Selective Elimination of High Constitutive Activity or Chemokine Binding in the Human Herpesvirus 8 Encoded Seven Transmembrane Oncogene ORF74 J. Biol. Chem., August 18, 2000; 275(34): 26309 - 26315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. H. Ho, N. Ganeshalingam, A. Rosenhouse-Dantsker, R. Osman, and M. C. Gershengorn Charged Residues at the Intracellular Boundary of Transmembrane Helices 2 and 3 Independently Affect Constitutive Activity of Kaposi's Sarcoma-associated Herpesvirus G Protein-coupled Receptor J. Biol. Chem., January 5, 2001; 276(2): 1376 - 1382. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
