SHIP1 and Lyn kinase negatively regulate integrin αIIbβ3 signaling in platelets

被引:69
作者
Maxwell, MJ
Yuan, YP
Anderson, KE
Hibbs, ML
Salem, HH
Jackson, SP [1 ]
机构
[1] Monash Univ, Box Hill Hosp, Dept Med, Australian Ctr Blood Dis, Melbourne, Vic 3128, Australia
[2] Royal Melbourne Hosp, Ludwig Inst Canc Res, Melbourne Tumour Biol Branch, Melbourne, Vic 3050, Australia
关键词
D O I
10.1074/jbc.M400746200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Integrin alpha(IIb)beta(3) 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 alpha(IIb)beta(3) 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 alpha(IIb)beta(3)-dependent phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P-3) 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)P-3 metabolism down-regulates the stability of integrin alpha(IIb)beta(3)-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 alpha(IIb)beta(3) adhesive and signaling function.
引用
收藏
页码:32196 / 32204
页数:9
相关论文
共 63 条
  • [1] Src kinase activation by direct interaction with the integrin β cytoplasmic domain
    Arias-Salgado, EG
    Lizano, S
    Sarkar, S
    Brugge, JS
    Ginsberg, MH
    Shattil, SJ
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (23) : 13298 - 13302
  • [2] Activation of phospholipase C-γ by phosphatidylinositol 3,4,5-trisphosphate
    Bae, YS
    Cantley, LG
    Chen, CS
    Kim, SR
    Kwon, KS
    Rhee, SG
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (08) : 4465 - 4469
  • [3] A novel integrin-activated pathway forms PKB/Akt-stimulatory phosphatidylinositol 3,4-bisphosphate via phosphatidylinositol 3-phosphate in platelets
    Banfic, H
    Tang, XW
    Batty, IH
    Downes, CP
    Chen, CS
    Rittenhouse, SE
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (01) : 13 - 16
  • [4] The inositol 5′-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity
    Baran, CP
    Tridandapani, S
    Helgason, CD
    Humphries, RK
    Krystal, G
    Marsh, CB
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (40) : 38628 - 38636
  • [5] Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation
    Choudhri, TF
    Hoh, BL
    Zerwes, HG
    Prestigiacomo, CJ
    Kim, SC
    Connolly, ES
    Kottirsch, G
    Pinsky, DJ
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1998, 102 (07) : 1301 - 1310
  • [6] Platelet endothelial cell adhesion molecule-1 signaling inhibits the activation of human platelets
    Cicmil, M
    Thomas, JM
    Leduc, M
    Bon, C
    Gibbins, JM
    [J]. BLOOD, 2002, 99 (01) : 137 - 144
  • [7] CUNNINGHAM TW, 1990, J BIOL CHEM, V265, P21676
  • [8] The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase
    Damen, JE
    Liu, L
    Rosten, P
    Humphries, RK
    Jefferson, AB
    Majerus, PW
    Krystal, G
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (04) : 1689 - 1693
  • [9] SIP/SHIP inhibits Xenopus oocyte maturation induced by insulin and phosphatidylinositol 3-kinase
    DeuterReinhard, M
    Apell, G
    Pot, D
    Klippel, A
    Williams, LT
    Kavanaugh, WM
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (05) : 2559 - 2565
  • [10] CAPTURE BY CHEMICAL CROSS-LINKERS PROVIDES EVIDENCE THAT INTEGRIN ALPHA-IIB-BETA-3 FORMS A COMPLEX WITH PROTEIN-TYROSINE KINASES IN INTACT PLATELETS
    DORAHY, DJ
    BERNDT, MC
    BURNS, GF
    [J]. BIOCHEMICAL JOURNAL, 1995, 309 : 481 - 490