CLEC-2 activates Syk through dimerization

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CLEC-2 activates Syk through dimerization. / Hughes, Craig; Pollitt, Alice; Mori, Jun; Eble, JA; Tomlinson, Michael; Hartwig, JH; O'Callaghan, CA; Futterer, Klaus; Watson, Steve.

In: Blood, Vol. 115, No. 14, 12.02.2010, p. 2947-2955.

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@article{581878b1b0744c96a088f5b7676848a9,
title = "CLEC-2 activates Syk through dimerization",
abstract = "The C-type lectin receptor CLEC-2 activates platelets through Src and Syk tyrosine kinases, leading to tyrosine phosphorylation of downstream adapter proteins and effector enzymes, including phospholipase-C 2. Signaling is initiated through phosphorylation of a single conserved tyrosine located in a YxxL sequence in the CLEC-2 cytosolic tail. The signaling pathway used by CLEC-2 shares many similarities with that used by receptors that have 1 or more copies of an immunoreceptor tyrosine-based activation motif, defined by the sequence Yxx(L/I)x6-12Yxx(L/I), in their cytosolic tails or associated receptor chains. Phosphorylation of the conserved immunoreceptor tyrosine-based activation motif tyrosines promotes Syk binding and activation through binding of the Syk tandem SH2 domains. In this report, we present evidence using peptide pull-down studies, surface plasmon resonance, quantitative Western blotting, tryptophan fluorescence measurements, and competition experiments that Syk activation by CLEC-2 is mediated by the cross-linking through the tandem SH2 domains with a stoichiometry of 2:1. In support of this model, cross-linking and electron microscopy demonstrate that CLEC-2 is present as a dimer in resting platelets and converted to larger complexes on activation. This is a unique mode of activation of Syk by a single YxxL-containing receptor",
keywords = "dimerisation",
author = "Craig Hughes and Alice Pollitt and Jun Mori and JA Eble and Michael Tomlinson and JH Hartwig and CA O'Callaghan and Klaus Futterer and Steve Watson",
year = "2010",
month = feb,
day = "12",
doi = "10.1182/blood-2009-08-237834",
language = "English",
volume = "115",
pages = "2947--2955",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "14",

}

RIS

TY - JOUR

T1 - CLEC-2 activates Syk through dimerization

AU - Hughes, Craig

AU - Pollitt, Alice

AU - Mori, Jun

AU - Eble, JA

AU - Tomlinson, Michael

AU - Hartwig, JH

AU - O'Callaghan, CA

AU - Futterer, Klaus

AU - Watson, Steve

PY - 2010/2/12

Y1 - 2010/2/12

N2 - The C-type lectin receptor CLEC-2 activates platelets through Src and Syk tyrosine kinases, leading to tyrosine phosphorylation of downstream adapter proteins and effector enzymes, including phospholipase-C 2. Signaling is initiated through phosphorylation of a single conserved tyrosine located in a YxxL sequence in the CLEC-2 cytosolic tail. The signaling pathway used by CLEC-2 shares many similarities with that used by receptors that have 1 or more copies of an immunoreceptor tyrosine-based activation motif, defined by the sequence Yxx(L/I)x6-12Yxx(L/I), in their cytosolic tails or associated receptor chains. Phosphorylation of the conserved immunoreceptor tyrosine-based activation motif tyrosines promotes Syk binding and activation through binding of the Syk tandem SH2 domains. In this report, we present evidence using peptide pull-down studies, surface plasmon resonance, quantitative Western blotting, tryptophan fluorescence measurements, and competition experiments that Syk activation by CLEC-2 is mediated by the cross-linking through the tandem SH2 domains with a stoichiometry of 2:1. In support of this model, cross-linking and electron microscopy demonstrate that CLEC-2 is present as a dimer in resting platelets and converted to larger complexes on activation. This is a unique mode of activation of Syk by a single YxxL-containing receptor

AB - The C-type lectin receptor CLEC-2 activates platelets through Src and Syk tyrosine kinases, leading to tyrosine phosphorylation of downstream adapter proteins and effector enzymes, including phospholipase-C 2. Signaling is initiated through phosphorylation of a single conserved tyrosine located in a YxxL sequence in the CLEC-2 cytosolic tail. The signaling pathway used by CLEC-2 shares many similarities with that used by receptors that have 1 or more copies of an immunoreceptor tyrosine-based activation motif, defined by the sequence Yxx(L/I)x6-12Yxx(L/I), in their cytosolic tails or associated receptor chains. Phosphorylation of the conserved immunoreceptor tyrosine-based activation motif tyrosines promotes Syk binding and activation through binding of the Syk tandem SH2 domains. In this report, we present evidence using peptide pull-down studies, surface plasmon resonance, quantitative Western blotting, tryptophan fluorescence measurements, and competition experiments that Syk activation by CLEC-2 is mediated by the cross-linking through the tandem SH2 domains with a stoichiometry of 2:1. In support of this model, cross-linking and electron microscopy demonstrate that CLEC-2 is present as a dimer in resting platelets and converted to larger complexes on activation. This is a unique mode of activation of Syk by a single YxxL-containing receptor

KW - dimerisation

U2 - 10.1182/blood-2009-08-237834

DO - 10.1182/blood-2009-08-237834

M3 - Article

C2 - 20154219

VL - 115

SP - 2947

EP - 2955

JO - Blood

JF - Blood

SN - 0006-4971

IS - 14

ER -