Roles of Focal Adhesion Kinase PTK2 and Integrin αIIbβ3 Signaling in Collagen- and GPVI-Dependent Thrombus Formation under Shear
| Autor: | Jingnan Huang, Natalie J. Jooss, Delia I. Fernández, Albert Sickmann, Ángel García, Kanin Wichapong, Ingrid Dijkgraaf, Johan W. M. Heemskerk |
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| Přispěvatelé: | Biochemie, RS: Carim - B03 Cell biochemistry of thrombosis and haemostasis, RS: Carim - B01 Blood proteins & engineering |
| Rok vydání: | 2022 |
| Předmět: |
Blood Platelets
Platelet Aggregation PROTEIN Platelet Glycoprotein GPIIb-IIIa Complex Platelet Membrane Glycoproteins Focal Adhesion Kinase 1/metabolism Peptides/metabolism Platelet Glycoprotein GPIIb-IIIa Complex/metabolism Catalysis Inorganic Chemistry ACTIVATION Platelet Adhesiveness Collagen/metabolism CIB Focal Adhesion Protein-Tyrosine Kinases/metabolism Humans Physical and Theoretical Chemistry Molecular Biology Spectroscopy PP125(FAK) PLATELET-FUNCTION TYROSINE PHOSPHORYLATION thrombus formation Organic Chemistry focal adhesion kinase INHIBITOR GPR56/ADGRG1 Thrombosis General Medicine Platelet Activation Platelet Membrane Glycoproteins/metabolism Computer Science Applications Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases platelets CALCIUM-BINDING integrins Blood Platelets/metabolism Collagen Thrombosis/metabolism Peptides GPR56 PP125FAK |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 15; Pages: 8688 International journal of molecular sciences, 23(15):8688. Multidisciplinary Digital Publishing Institute (MDPI) |
| ISSN: | 1422-0067 1661-6596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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