SHIP1 and Lyn kinase negatively regulate integrin α IIbβ3 signaling in platelets

Mhairi J. Maxwell, Yuping Yuan, Karen E. Anderson, Margaret L. Hibbs, Hatem H. Salem, Shaun P. Jackson

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66 Citations (Scopus)

Abstract

Integrin αIIbβ3 plays a critical role in platelet function, promoting a broad range of functional responses including platelet adhesion, spreading, aggregation, clot retraction, and platelet procoagulant function. Signaling events operating downstream of this receptor (outside-in signaling) are important for these responses; however the mechanisms negatively regulating integrin αIIbβ3 signaling remain ill-defined. We demonstrate here a major role for the Src homology 2 domain-containing inositol 5-phosphatase (SHIP1) and Src family kinase, Lyn, in this process. Our studies on murine SHIP1 knockout platelets have defined a major role for this enzyme in regulating integrin αIIbβ3-dependent phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) accumulation, necessary for a cytosolic calcium response and platelet spreading. SHIP1 phosphorylation and PtdIns(3,4,5)P3 metabolism is partially regulated through Lyn kinase, resulting in an enhanced calcium flux and spreading response in Lyn-deficient mouse platelets. Analysis of platelet adhesion dynamics under physiological blood flow conditions revealed an important role for SHIP1 in regulating platelet adhesion on fibrinogen. Specifically, SHIP1-dependent PtdIns(3,4,5)P3 metabolism down-regulates the stability of integrin αIIbβ3-fibrinogen adhesive bonds, leading to a decrease in the proportion of platelets forming shear-resistant adhesion contacts. These studies define a major role for SHIP1 and Lyn as negative regulators of integrin αIIbβ3 adhesive and signaling function.

Original languageEnglish
Pages (from-to)32196-32204
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number31
DOIs
Publication statusPublished - 30 Jul 2004

Cite this

@article{c4fbe50bf7da4c81a7684a44819eda57,
title = "SHIP1 and Lyn kinase negatively regulate integrin α IIbβ3 signaling in platelets",
abstract = "Integrin αIIbβ3 plays a critical role in platelet function, promoting a broad range of functional responses including platelet adhesion, spreading, aggregation, clot retraction, and platelet procoagulant function. Signaling events operating downstream of this receptor (outside-in signaling) are important for these responses; however the mechanisms negatively regulating integrin αIIbβ3 signaling remain ill-defined. We demonstrate here a major role for the Src homology 2 domain-containing inositol 5-phosphatase (SHIP1) and Src family kinase, Lyn, in this process. Our studies on murine SHIP1 knockout platelets have defined a major role for this enzyme in regulating integrin αIIbβ3-dependent phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) accumulation, necessary for a cytosolic calcium response and platelet spreading. SHIP1 phosphorylation and PtdIns(3,4,5)P3 metabolism is partially regulated through Lyn kinase, resulting in an enhanced calcium flux and spreading response in Lyn-deficient mouse platelets. Analysis of platelet adhesion dynamics under physiological blood flow conditions revealed an important role for SHIP1 in regulating platelet adhesion on fibrinogen. Specifically, SHIP1-dependent PtdIns(3,4,5)P3 metabolism down-regulates the stability of integrin αIIbβ3-fibrinogen adhesive bonds, leading to a decrease in the proportion of platelets forming shear-resistant adhesion contacts. These studies define a major role for SHIP1 and Lyn as negative regulators of integrin αIIbβ3 adhesive and signaling function.",
author = "Maxwell, {Mhairi J.} and Yuping Yuan and Anderson, {Karen E.} and Hibbs, {Margaret L.} and Salem, {Hatem H.} and Jackson, {Shaun P.}",
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language = "English",
volume = "279",
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SHIP1 and Lyn kinase negatively regulate integrin α IIbβ3 signaling in platelets. / Maxwell, Mhairi J.; Yuan, Yuping; Anderson, Karen E.; Hibbs, Margaret L.; Salem, Hatem H.; Jackson, Shaun P.

In: Journal of Biological Chemistry, Vol. 279, No. 31, 30.07.2004, p. 32196-32204.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - SHIP1 and Lyn kinase negatively regulate integrin α IIbβ3 signaling in platelets

AU - Maxwell, Mhairi J.

AU - Yuan, Yuping

AU - Anderson, Karen E.

AU - Hibbs, Margaret L.

AU - Salem, Hatem H.

AU - Jackson, Shaun P.

PY - 2004/7/30

Y1 - 2004/7/30

N2 - Integrin αIIbβ3 plays a critical role in platelet function, promoting a broad range of functional responses including platelet adhesion, spreading, aggregation, clot retraction, and platelet procoagulant function. Signaling events operating downstream of this receptor (outside-in signaling) are important for these responses; however the mechanisms negatively regulating integrin αIIbβ3 signaling remain ill-defined. We demonstrate here a major role for the Src homology 2 domain-containing inositol 5-phosphatase (SHIP1) and Src family kinase, Lyn, in this process. Our studies on murine SHIP1 knockout platelets have defined a major role for this enzyme in regulating integrin αIIbβ3-dependent phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) accumulation, necessary for a cytosolic calcium response and platelet spreading. SHIP1 phosphorylation and PtdIns(3,4,5)P3 metabolism is partially regulated through Lyn kinase, resulting in an enhanced calcium flux and spreading response in Lyn-deficient mouse platelets. Analysis of platelet adhesion dynamics under physiological blood flow conditions revealed an important role for SHIP1 in regulating platelet adhesion on fibrinogen. Specifically, SHIP1-dependent PtdIns(3,4,5)P3 metabolism down-regulates the stability of integrin αIIbβ3-fibrinogen adhesive bonds, leading to a decrease in the proportion of platelets forming shear-resistant adhesion contacts. These studies define a major role for SHIP1 and Lyn as negative regulators of integrin αIIbβ3 adhesive and signaling function.

AB - Integrin αIIbβ3 plays a critical role in platelet function, promoting a broad range of functional responses including platelet adhesion, spreading, aggregation, clot retraction, and platelet procoagulant function. Signaling events operating downstream of this receptor (outside-in signaling) are important for these responses; however the mechanisms negatively regulating integrin αIIbβ3 signaling remain ill-defined. We demonstrate here a major role for the Src homology 2 domain-containing inositol 5-phosphatase (SHIP1) and Src family kinase, Lyn, in this process. Our studies on murine SHIP1 knockout platelets have defined a major role for this enzyme in regulating integrin αIIbβ3-dependent phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) accumulation, necessary for a cytosolic calcium response and platelet spreading. SHIP1 phosphorylation and PtdIns(3,4,5)P3 metabolism is partially regulated through Lyn kinase, resulting in an enhanced calcium flux and spreading response in Lyn-deficient mouse platelets. Analysis of platelet adhesion dynamics under physiological blood flow conditions revealed an important role for SHIP1 in regulating platelet adhesion on fibrinogen. Specifically, SHIP1-dependent PtdIns(3,4,5)P3 metabolism down-regulates the stability of integrin αIIbβ3-fibrinogen adhesive bonds, leading to a decrease in the proportion of platelets forming shear-resistant adhesion contacts. These studies define a major role for SHIP1 and Lyn as negative regulators of integrin αIIbβ3 adhesive and signaling function.

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M3 - Article

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JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

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