SHIP1 and Lyn Kinase Negatively Regulate Integrin alpha IIb beta 3 signaling in platelets.
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)P(3) 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.
Maxwell
Mhairi J
MJ
Australian Centre for Blood Diseases, Department of Medicine, Monash University, Box Hill Hospital, Victoria 3128, Australia.
Yuan
Yuping
Y
Anderson
Karen E
KE
Hibbs
Margaret L
ML
Salem
Hatem H
HH
Jackson
Shaun P
SP
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation; D004912:Erythrocytes / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D016023:Integrins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D010973:Platelet Adhesiveness; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D011233:Precipitin Tests; D015398:Signal Transduction; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D016023:Integrins; D018129:Phosphatidylinositol Phosphates; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C060974:phosphatidylinositol 3,4,5-triphosphate; D014443:Tyrosine; D005340:Fibrinogen; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D002118:Calcium