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Signal Transduction and Cell Transformation Induced by the CXCR2 and the Kaposi Sarcoma Receptors

I.U. Schraufstätter, R.C. Hoch, M. Burger, Z.G. Oades, H. Takamori

Recently, a constitutively activated 7-membrane-spanning viral receptor, Kaposi GPCR, that causes cell transformation was cloned form Kaposi sarcoma. The receptor is part of the genome of human herpesvirus 8.

Expression of Kaposi GPCR in NIH3T3 cells led to focus formation and anchorage-independent growth. We also transfected NIH3T3 cells with CXCR2 (IL-8 receptor B), which shares 26% sequence identity with Kaposi GPCR. Both full-length CXCR2 and a truncated form that cannot be phosphorylated and that causes prolonged activation supported focus formation, presumably because of mouse KC, the mouse equivalent of gro-, which is produced by NIH3T3 cells and which stimulates human CXCR2. A similar growth-promoting loop exists in various melanoma cells that both produce IL-8 and express CXCR2.

We also found a caveolin-binding motif in the seventh membrane-spanning domain of the CXCR2: Tyr309-Ala-Phe-Ile-Gly-Gln-Lys-Phe. This finding led us to study colocalization between the CXCR2 and caveolin. As revealed by confocal microscopy, after IL-8 was added to RBL2H3 cells expressing the CXCR2, the receptor started to colocalize with caveolin within 3--4 minutes and then gradually disappeared from the surface of the cells. A Tyr309Ala CXCR2 mutant colocalized with caveolin in the absence of ligand but had poor G-protein coupling and was not internalized. The truncated receptor had a weak association with caveolin. These results suggest that caveolar localization serves as a turnoff for the signal transduction machinery.

PUBLICATIONS

DiScipio, R.D., Daffern, P.J., Schraufstätter, I.U., Sriramarao, P. Human complement factor H is an adhesion ligand for human neutrophils but not eosinophils. J. Immunol. 160:4057, 1998.

Schraufstätter, I.U. Chemokine receptors. In: Chemokines and Skin. Kownatzki, E., Norgauer, J. (Eds.). Birkhauser, Basel, Switzerland, 1998, p. 23.

Schraufstätter, I.U., Oades, Z.G., Hoch, R.C., Takamori, H., Burger, M. Importance of the carboxy-terminus of the CXCR2 for signal transduction. Biochem. Biophys. Res. Commun. 244:243, 1998.