Roles of Focal Adhesion Kinase PTK2 and Integrin αIIbβ3 Signaling in Collagen- and GPVI-Dependent Thrombus Formation under Shear

Jingnan Huang, Natalie J Jooss, Delia I Fernández, Albert Sickmann, Ángel García, Kanin Wichapong, Ingrid Dijkgraaf, Johan W M Heemskerk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Glycoprotein (GP)VI and integrin αIIbβ3 are key signaling receptors in collagen-dependent platelet aggregation and in arterial thrombus formation under shear. The multiple downstream signaling pathways are still poorly understood. Here, we focused on disclosing the integrin-dependent roles of focal adhesion kinase (protein tyrosine kinase 2, PTK2), the shear-dependent collagen receptor GPR56 (ADGRG1 gene), and calcium and integrin-binding protein 1 (CIB1). We designed and synthetized peptides that interfered with integrin αIIb binding (pCIB and pCIBm) or mimicked the activation of GPR56 (pGRP). The results show that the combination of pGRP with PTK2 inhibition or of pGRP with pCIB > pCIBm in additive ways suppressed collagen- and GPVI-dependent platelet activation, thrombus buildup, and contraction. Microscopic thrombus formation was assessed by eight parameters (with script descriptions enclosed). The suppressive rather than activating effects of pGRP were confined to blood flow at a high shear rate. Blockage of PTK2 or interference of CIB1 no more than slightly affected thrombus formation at a low shear rate. Peptides did not influence GPVI-induced aggregation and Ca2+ signaling in the absence of shear. Together, these data reveal a shear-dependent signaling axis of PTK2, integrin αIIbβ3, and CIB1 in collagen- and GPVI-dependent thrombus formation, which is modulated by GPR56 and exclusively at high shear. This work thereby supports the role of PTK2 in integrin αIIbβ3 activation and signaling.

Original languageEnglish
Article number8688
Number of pages19
JournalInternational journal of molecular sciences
Volume23
Issue number15
DOIs
Publication statusPublished - 4 Aug 2022

Keywords

  • Blood Platelets/metabolism
  • Collagen/metabolism
  • Focal Adhesion Kinase 1/metabolism
  • Focal Adhesion Protein-Tyrosine Kinases/metabolism
  • Humans
  • Peptides/metabolism
  • Platelet Activation
  • Platelet Adhesiveness
  • Platelet Aggregation
  • Platelet Glycoprotein GPIIb-IIIa Complex/metabolism
  • Platelet Membrane Glycoproteins/metabolism
  • Thrombosis/metabolism
  • PP125(FAK)
  • ACTIVATION
  • PROTEIN
  • PLATELET-FUNCTION
  • integrins
  • thrombus formation
  • INHIBITOR
  • CIB
  • GPR56/ADGRG1
  • GPR56
  • TYROSINE PHOSPHORYLATION
  • platelets
  • focal adhesion kinase
  • CALCIUM-BINDING
  • PP125FAK

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