Abstract
In this study, we investigated the functional role of the localization of human OTR in caveolin-1 enriched membrane domains. Biochemical fractionation of MDCK cells stably expressing the WT OTR-GFP indicated that only minor quantities of receptor are partitioned in caveolin-1 enriched domains. However, when fused to caveolin-2, the OTR protein proved to be exclusively localized in caveolin-1 enriched fractions, where it bound the agonist with increased affinity and efficiently coupled to Gαq/11. Interestingly, the chimeric protein was unable to undergo agonist-induced internalization and remained confined to the plasma membrane even after prolonged agonist exposure (120 min). A striking difference in receptor stimulation was observed when the OT-induced effect on cell proliferation was analysed: stimulation of the human WT OTR inhibited cell growth, whereas the chimeric protein had a proliferative effect. These data indicate that the localization of human OTR in caveolin-1 enriched microdomains radically alters its regulatory effects on cell growth; the fraction of OTR residing in caveolar structures may therefore play a crucial role in regulating cell proliferation.
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Acknowledgements
We thank Dr V Pliska helpfully commenting on the binding assays and Prof N Borgese for critically reading the manuscript. This work was supported by a grant from the AIRC (Italian Association for Cancer Research) to B Chini and a MURST grant (Cofin 2000) to M Parenti.
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Guzzi, F., Zanchetta, D., Cassoni, P. et al. Localization of the human oxytocin receptor in caveolin-1 enriched domains turns the receptor-mediated inhibition of cell growth into a proliferative response. Oncogene 21, 1658–1667 (2002). https://doi.org/10.1038/sj.onc.1205219
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DOI: https://doi.org/10.1038/sj.onc.1205219
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