PTP-1B is an essential positive regulator of platelet integrin signaling.
Outside-in integrin alphaIIbbeta3 signaling is required for normal platelet thrombus formation and is triggered by c-Src activation through an unknown mechanism. In this study, we demonstrate an essential role for protein-tyrosine phosphatase (PTP)-1B in this process. In resting platelets, c-Src forms a complex with alphaIIbbeta3 and Csk, which phosphorylates c-Src tyrosine 529 to maintain c-Src autoinhibition. Fibrinogen binding to alphaIIbbeta3 triggers PTP-1B recruitment to the alphaIIbbeta3-c-Src-Csk complex in a manner that is dependent on c-Src and specific tyrosine (tyrosine 152 and 153) and proline (proline 309 and 310) residues in PTP-1B. Studies of PTP-1B-deficient mouse platelets indicate that PTP-1B is required for fibrinogen-dependent Csk dissociation from alphaIIbbeta3, dephosphorylation of c-Src tyrosine 529, and c-Src activation. Furthermore, PTP-1B-deficient platelets are defective in outside-in alphaIIbbeta3 signaling in vitro as manifested by poor spreading on fibrinogen and decreased clot retraction, and they exhibit ineffective Ca2+ signaling and thrombus formation in vivo. Thus, PTP-1B is an essential positive regulator of the initiation of outside-in alphaIIbbeta3 signaling in platelets.
Arias-Salgado
Elena Garcia
EG
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Haj
Fawaz
F
Dubois
Christophe
C
Moran
Barry
B
Kasirer-Friede
Ana
A
Furie
Barbara C
BC
Furie
Bruce
B
Neel
Benjamin G
BG
Shattil
Sanford J
SJ
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D010770:Phosphotransferases / Q000378:metabolism; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases
D046912:Multiprotein Complexes; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011518:Proto-Oncogene Proteins; D010770:Phosphotransferases; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse