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

This Article Full Text Full Text (PDF) Buy All Versions of this Article: fj.09-131367v1 23/12/4069    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 Google Scholar Articles by El Firar, A. Articles by Laburthe, M. PubMed PubMed Citation Articles by El Firar, A. Articles by Laburthe, M.

Discovery of a functional immunoreceptor tyrosine-based switch motif in a 7-transmembrane-spanning receptor: role in the orexin receptor OX1R-driven apoptosis

INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Paris, France; and Université Paris 7 Denis Diderot, UMR S773, Paris, France

¹ Correspondence: INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, F-75018, Paris. E-mail: M.L., marc.laburthe{at}inserm.fr; T.V., thierry.voisin{at}inserm.fr

The orexin neuropeptides promote robust apoptosis in cancer cells. We have recently shown that the 7-transmembrane-spanning orexin receptor OX1R mediates apoptosis through an original mechanism. OX1R is equipped with a tyrosine-based inhibitory motif ITIM, which is tyrosine-phosphorylated on receptor activation, allowing the recruitment and activation of the tyrosine phosphatase SHP-2, leading to apoptosis. We show here that another motif, immunoreceptor tyrosine-based switch motif (ITSM), is present in OX1R and is mandatory for OX1R-mediated apoptosis. This conclusion is based on the following observations: 1) a canonical ITSM sequence is present in the first intracellular loop of OX1R; 2) mutation of Y⁸³ to F within ITSM abolished OX1R-mediated apoptosis but did not alter orexin-induced inositol phosphate formation or calcium transient via coupling of OX1R to G_q protein; 3) mutation of Y⁸³ to F further abolished orexin-induced tyrosine phosphorylation in ITSM and subsequent recruitment of SHP-2 by the receptor. Finally, we developed a structural model of OX1R showing that the spatial localization of phosphotyrosines in ITSM and ITIM in OX1R is compatible with their interaction with the two SH2 domains of SHP-2. These data represent the first evidence for a functional role of an ITSM in a 7-transmembrane-spanning receptor.—El Firar, A., Voisin, T., Rouyer-Fessard, C., Ostuni, M. A., Couvineau, A., Laburthe, M. Discovery of a functional immunoreceptor tyrosine-based switch motif in a 7-transmembrane-spanning receptor: role in the orexin receptor OX1R-driven apoptosis.

Key Words: neuropeptide • G protein-coupled receptor • tyrosine-based motifs • protein tyrosine phosphatase • SHP-2