HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Free Full Text (PDF) Free All Versions of this Article: fj.07-098723v1 22/6/1993    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Voisin, T. Articles by Laburthe, M. Search for Related Content PubMed PubMed Citation Articles by Voisin, T. Articles by Laburthe, M.

A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor OX1R for orexins and drives apoptosis: a novel mechanism

INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, and Université Paris Diderot, UMR S 773, Paris, France

¹Correspondence: INSERM, U773, CRB3, Paris, F-75018, France; Université Paris Diderot, UMR S 773, F-75018, Paris, France. E-mail: tvoisin{at}bichat.inserm.fr

Orexins acting at the G protein-coupled receptor (GPCR) OX1R have recently been shown to promote dramatic apoptosis in cancer cells. We report here that orexin-induced apoptosis is driven by an immunoreceptor tyrosine-based inhibitory motif (ITIM) (IIY³⁵⁸NFL) present in the OX1R. This effect is mediated by SHP-2 phosphatase recruitment via a mechanism that requires Gq protein but is independent of phospholipase C activation. This is based on the following observations: 1) mutation of Y³⁵⁸ into F abolished orexin-induced tyrosine phosphorylation in ITIM, orexin-induced apoptosis, and uncoupled OX1R from Gq protein in transfected Chinese hamster ovary (CHO) cells; 2) orexin-induced apoptosis in CHO cells expressing recombinant OX1R and in colon cancer cells expressing the native receptor was abolished by treatment with the tyrosine phosphatase inhibitor PAO and by transfection with a dominant-negative mutant of SHP-2; 3) orexins were unable to promote apoptosis in fibroblast cells invalidated for the Gq subunit and transfected with OX1R cDNA, whereas they promoted apoptosis in cells equipped with Gq and OX1R; and 4) the phospholipase C inhibitor U-73122 blocked orexin-stimulated inositol phosphate formation, whereas it had no effect on orexin-induced apoptosis in CHO cells expressing OX1R. These data unravel a novel mechanism, whereby ITIM-expressing GPCRs may trigger apoptosis.—Voisin, T., El Firar, A., Rouyer-Fessard, C., Gratio, V., Laburthe, M. A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor OX1R for orexins and drives apoptosis: a novel mechanism.

Key Words: hypocretin • cancer cell death • colon cancer • tyrosine phosphatase • SHP-2

This article has been cited by other articles:

				A. El Firar, T. Voisin, C. Rouyer-Fessard, M. A. Ostuni, A. Couvineau, and M. Laburthe Discovery of a functional immunoreceptor tyrosine-based switch motif in a 7-transmembrane-spanning receptor: role in the orexin receptor OX1R-driven apoptosis FASEB J, December 1, 2009; 23(12): 4069 - 4080. [Abstract] [Full Text] [PDF]

				C. Orabona, M. T. Pallotta, C. Volpi, F. Fallarino, C. Vacca, R. Bianchi, M. L. Belladonna, M. C. Fioretti, U. Grohmann, and P. Puccetti SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis PNAS, December 30, 2008; 105(52): 20828 - 20833. [Abstract] [Full Text] [PDF]