Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B

Research output: Contribution to journalArticle

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Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B. / Voegtle, Timo; Sharma, Sumana; Mori, Jun; Nagy, Zoltan; Semeniak, Daniela; Scandola, Cyril ; Geer, Mitchell; Smith, Christopher; Lane, Jordan ; Pollack, Scott; Lassila, Riitta ; Jouppila, Annukka; Barr, Alastair J.; Ogg, Derek J; Howard, Tina D ; McMiken, Helen; Warwicker, Juli; Geh, Catherine; Rowlinson, Rachel ; Abbott, W. Mark; Eckly, Anita; Schulze, Harold; Wright, Gavin J ; Mazharian, Alexandra; Futterer, Klaus; Sundaresan, Rajesh; Douglas, Michael; Senis, Yotis.

In: Elife, Vol. 8, 46840, 22.08.2019, p. 1-43.

Research output: Contribution to journalArticle

Harvard

Voegtle, T, Sharma, S, Mori, J, Nagy, Z, Semeniak, D, Scandola, C, Geer, M, Smith, C, Lane, J, Pollack, S, Lassila, R, Jouppila, A, Barr, AJ, Ogg, DJ, Howard, TD, McMiken, H, Warwicker, J, Geh, C, Rowlinson, R, Abbott, WM, Eckly, A, Schulze, H, Wright, GJ, Mazharian, A, Futterer, K, Sundaresan, R, Douglas, M & Senis, Y 2019, 'Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B', Elife, vol. 8, 46840, pp. 1-43. https://doi.org/10.7554/eLife.46840

APA

Voegtle, T., Sharma, S., Mori, J., Nagy, Z., Semeniak, D., Scandola, C., Geer, M., Smith, C., Lane, J., Pollack, S., Lassila, R., Jouppila, A., Barr, A. J., Ogg, D. J., Howard, T. D., McMiken, H., Warwicker, J., Geh, C., Rowlinson, R., ... Senis, Y. (2019). Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B. Elife, 8, 1-43. [46840]. https://doi.org/10.7554/eLife.46840

Vancouver

Author

Voegtle, Timo ; Sharma, Sumana ; Mori, Jun ; Nagy, Zoltan ; Semeniak, Daniela ; Scandola, Cyril ; Geer, Mitchell ; Smith, Christopher ; Lane, Jordan ; Pollack, Scott ; Lassila, Riitta ; Jouppila, Annukka ; Barr, Alastair J. ; Ogg, Derek J ; Howard, Tina D ; McMiken, Helen ; Warwicker, Juli ; Geh, Catherine ; Rowlinson, Rachel ; Abbott, W. Mark ; Eckly, Anita ; Schulze, Harold ; Wright, Gavin J ; Mazharian, Alexandra ; Futterer, Klaus ; Sundaresan, Rajesh ; Douglas, Michael ; Senis, Yotis. / Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B. In: Elife. 2019 ; Vol. 8. pp. 1-43.

Bibtex

@article{5dcac674e7b54fa9873838f3bfa908f8,
title = "Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B",
abstract = "The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of G6b-B results in severe macrothrombocytopenia, myelofibrosis and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically-modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans.",
keywords = "Platelets, ITIM-Receptor, G6b-B, heparan sulfate, heparin, perlecan, signaling, tyrosine phosphatases, platelets, ITIM-receptor, mouse, cell biology, chemical biology, biochemistry, human",
author = "Timo Voegtle and Sumana Sharma and Jun Mori and Zoltan Nagy and Daniela Semeniak and Cyril Scandola and Mitchell Geer and Christopher Smith and Jordan Lane and Scott Pollack and Riitta Lassila and Annukka Jouppila and Barr, {Alastair J.} and Ogg, {Derek J} and Howard, {Tina D} and Helen McMiken and Juli Warwicker and Catherine Geh and Rachel Rowlinson and Abbott, {W. Mark} and Anita Eckly and Harold Schulze and Wright, {Gavin J} and Alexandra Mazharian and Klaus Futterer and Rajesh Sundaresan and Michael Douglas and Yotis Senis",
year = "2019",
month = aug,
day = "22",
doi = "10.7554/eLife.46840",
language = "English",
volume = "8",
pages = "1--43",
journal = "Elife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

RIS

TY - JOUR

T1 - Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B

AU - Voegtle, Timo

AU - Sharma, Sumana

AU - Mori, Jun

AU - Nagy, Zoltan

AU - Semeniak, Daniela

AU - Scandola, Cyril

AU - Geer, Mitchell

AU - Smith, Christopher

AU - Lane, Jordan

AU - Pollack, Scott

AU - Lassila, Riitta

AU - Jouppila, Annukka

AU - Barr, Alastair J.

AU - Ogg, Derek J

AU - Howard, Tina D

AU - McMiken, Helen

AU - Warwicker, Juli

AU - Geh, Catherine

AU - Rowlinson, Rachel

AU - Abbott, W. Mark

AU - Eckly, Anita

AU - Schulze, Harold

AU - Wright, Gavin J

AU - Mazharian, Alexandra

AU - Futterer, Klaus

AU - Sundaresan, Rajesh

AU - Douglas, Michael

AU - Senis, Yotis

PY - 2019/8/22

Y1 - 2019/8/22

N2 - The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of G6b-B results in severe macrothrombocytopenia, myelofibrosis and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically-modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans.

AB - The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation. Loss of G6b-B results in severe macrothrombocytopenia, myelofibrosis and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically-modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans.

KW - Platelets

KW - ITIM-Receptor

KW - G6b-B

KW - heparan sulfate

KW - heparin

KW - perlecan

KW - signaling

KW - tyrosine phosphatases

KW - platelets

KW - ITIM-receptor

KW - mouse

KW - cell biology

KW - chemical biology

KW - biochemistry

KW - human

UR - http://www.scopus.com/inward/record.url?scp=85072509074&partnerID=8YFLogxK

U2 - 10.7554/eLife.46840

DO - 10.7554/eLife.46840

M3 - Article

C2 - 31436532

VL - 8

SP - 1

EP - 43

JO - Elife

JF - Elife

SN - 2050-084X

M1 - 46840

ER -