title: Cutting edge: TREM-like transcript-1, a platelet immunoreceptor tyrosine-based inhibition motif encoding costimulatory immunoreceptor that enhances, rather than inhibits, calcium signaling via SHP-2.
abstract: To date, immunoreceptor tyrosine-based inhibition motifs (ITIMs) have been shown to mediate inhibitory properties. We report a novel triggering receptor expressed on myeloid cells (TREM) family member, TREM-like transcript-1 (TLT1), which differs from the activating members because its cytoplasmic tail contains two ITIMs at Y245 and Y281. A TLT1 splice variant (TLT1sp) encodes a different cytoplasmic tail lacking ITIMs. Both isoforms are expressed in resting platelet alpha-granules, which are up-regulated to the cell surface following activation. TLT1 recruited Src homology 2 domain-containing tyrosine phosphatase (SHP)-2 to the "classical" ITIM (Y281) but not the "nonclassical" ITIM (Y245). In contrast to previously characterized ITIM receptors, TLT1 enhanced, rather than inhibited, FcepsilonRI-mediated calcium signaling in rat basophilic leukemia cells, a property dependent on the SHP-2 recruiting classical Y281 ITIM. Therefore, TLT1 represents a new costimulatory ITIM immunoreceptor and is the second ITIM-bearing receptor to be identified in platelets after platelet endothelial cell adhesion molecule-1.
authors.affiliation: Cambridge Institute for Medical Research, Wellcome Trust, Addenbrookes Hospital, Cambridge, United Kingdom. adb44@cam.ac.uk
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Barrow
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Astoul
authors.forename: Andres
authors.initials: A
authors.lastname: Floto
authors.forename: Gary
authors.initials: G
authors.lastname: Brooke
authors.forename: Ingrid A M
authors.initials: IA
authors.lastname: Relou
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Jennings
authors.forename: Kenneth G C
authors.initials: KG
authors.lastname: Smith
authors.forename: Willem
authors.initials: W
authors.lastname: Ouwehand
authors.forename: Richard W
authors.initials: RW
authors.lastname: Farndale
authors.forename: Denis R
authors.initials: DR
authors.lastname: Alexander
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
mesh_terms: D017398:Alternative Splicing; D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D001792:Blood Platelets / Q000276:immunology* / Q000378:metabolism*; D020013:Calcium Signaling / Q000276:immunology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007399:Interphase / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008970:Molecular Weight; D019007:P-Selectin / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017455:Receptors, IgE / Q000502:physiology; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*; D018909:src Homology Domains / Q000276:immunology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D019007:P-Selectin; D010446:Peptide Fragments; D020033:Protein Isoforms; D017455:Receptors, IgE; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; C086309:thrombin receptor peptide SFLLRNP; D014443:Tyrosine; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases