title: The C-type lectin receptors CLEC-2 and Dectin-1, but not DC-SIGN, signal via a novel YXXL-dependent signaling cascade.
abstract: The two lectin receptors, CLEC-2 and Dectin-1, have been shown to signal through a Syk-dependent pathway, despite the presence of only a single YXXL in their cytosolic tails. In this study, we show that stimulation of CLEC-2 in platelets and in two mutant cell lines is dependent on the YXXL motif and on proteins that participate in signaling by immunoreceptor tyrosine-based activation motif receptors, including Src, Syk, and Tec family kinases, and on phospholipase Cgamma. Strikingly, mutation of either Src homology (SH) 2 domain of Syk blocks signaling by CLEC-2 despite the fact that it has only a single YXXL motif. Furthermore, signaling by CLEC-2 is only partially dependent on the BLNK/SLP-76 family of adapter proteins in contrast to that of immunoreceptor tyrosine-based activation motif receptors. The C-type lectin receptor, Dectin-1, which contains a YXXL motif preceded by the same four amino acids as for CLEC-2 (DEDG), signals like CLEC-2 and also requires the two SH2 domains of Syk and is only partially dependent on the BLNK/SLP-76 family of adapters. In marked contrast, the C-type lectin receptor, DC-SIGN, which has a distinct series of amino acids preceding a single YXXL, signals independent of this motif. A mutational analysis of the DEDG sequence of CLEC-2 revealed that the glycine residue directly upstream of the YXXL tyrosine is important for CLEC-2 signaling. These results demonstrate that CLEC-2 and Dectin-1 signal through a single YXXL motif that requires the tandem SH2 domains of Syk but is only partially dependent on the SLP-76/BLNK family of adapters.
authors.affiliation: Centre for Cardiovascular Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Gemma L J
authors.initials: GL
authors.lastname: Fuller
authors.forename: Jennifer A E
authors.initials: JA
authors.lastname: Williams
authors.forename: Michael G
authors.initials: MG
authors.lastname: Tomlinson
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Eble
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Hanna
authors.forename: Stefan
authors.initials: S
authors.lastname: Pöhlmann
authors.forename: Katsue
authors.initials: K
authors.lastname: Suzuki-Inoue
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ozaki
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Pearce
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000072377:Syk Kinase; D018909:src Homology Domains / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; D000099181:Dectin-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011505:Protein-Tyrosine Kinases; D011956:Receptors, Cell Surface; D000072377:Syk Kinase; D019061:src-Family Kinases; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; D000099181:Dectin-1; C113939:B cell linker protein; C104778:CLEC2B protein, human; C089848:Tec protein-tyrosine kinase; C000606896:SYK protein, human