PTP-1B is an essential positive regulator of platelet integrin signaling

J Cell Biol. 2005 Aug 29;170(5):837-45. doi: 10.1083/jcb.200503125. Epub 2005 Aug 22.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Platelets / metabolism*
  • CSK Tyrosine-Protein Kinase
  • Cell Line
  • Enzyme Activation
  • Humans
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes
  • Phosphotransferases / metabolism
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases / metabolism*
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction / physiology*
  • src-Family Kinases

Substances

  • Multiprotein Complexes
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Proto-Oncogene Proteins
  • Phosphotransferases
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • PTPN1 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatases
  • Ptpn1 protein, mouse