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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
Author(s) -
Voisin Thierry,
Firar Aadil El,
RouyerFessard Christiane,
Gratio Valérie,
Laburthe Marc
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-098723
Subject(s) - g protein coupled receptor , protein tyrosine phosphatase , microbiology and biotechnology , transfection , chinese hamster ovary cell , phospholipase c , biology , immunoreceptor tyrosine based activation motif , receptor , orexin receptor , apoptosis , gq alpha subunit , orexin , signal transduction , chemistry , biochemistry , sh2 domain , neuropeptide , gene
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) (IIY 358 NFL) 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 Y 358 into F abolished orexin‐induced tyrosine phosphorylation in ITIM, orexin‐induced apopto sis, 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 Gαq subunit and transfected with OX1R cDNA, whereas they promoted apoptosis in cells equipped with Gαq 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 apo ptosis: a novel mechanism. FASEB J. 22, 1993–2002 (2008)