Abstract
The platelet receptors, glycoprotein VI (GPVI) and integrin alpha 2 beta 1 jointly control collagen-dependent thrombus formation via protein tyrosine kinases. It is unresolved to which extent the ITIM (immunoreceptor tyrosine-based inhibitory motif) receptor PECAM1 and its downstream acting protein tyrosine phosphatase PTPN11 interfere in this process. Here, we hypothesized that integrin alpha 2 beta 1 has a co-regulatory role in the PECAM1- and PTPN11-dependent restraint of thrombus formation. We investigated platelet activation under flow on collagens with a different GPVI dependency and using integrin alpha 2 beta 1 blockage. Blood was obtained from healthy subjects and from patients with Noonan syndrome with a gain-of-function mutation of PTPN11 and variable bleeding phenotype. On collagens with decreasing GPVI activity (types I, III, IV), the surface-dependent inhibition of PECAM1 did not alter thrombus parameters using control blood. Blockage of alpha 2 beta 1 generally reduced thrombus parameters, most effectively on collagen IV. Strikingly, simultaneous inhibition of PECAM1 and alpha 2 beta 1 led to a restoration of thrombus formation, indicating that the suppressing signaling effect of PECAM1 is masked by the platelet-adhesive receptor alpha 2 beta 1. Blood from 4 out of 6 Noonan patients showed subnormal thrombus formation on collagen IV. In these patients, effects of alpha 2 beta 1 blockage were counterbalanced by PECAM1 inhibition to a normal phenotype. In summary, we conclude that the suppression of GPVI-dependent thrombus formation by either PECAM1 or a gain-of-function of PTPN11 can be overruled by alpha 2 beta 1 engagement.
Original language | English |
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Article number | 44 |
Number of pages | 14 |
Journal | Cellular and Molecular Life Sciences |
Volume | 81 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2024 |
Keywords
- Collagens
- PTPN11
- SHP2
- Noonan syndrome
- Microspots
- Microfluidics
- CELL ADHESION MOLECULE-1
- TYROSINE-PHOSPHATASE
- MONOCLONAL-ANTIBODY
- ALPHA(2)BETA(1) DENSITY
- INHIBITORY RECEPTOR
- NEGATIVE REGULATOR
- COLLAGEN RECEPTOR
- PTPN11 MUTATIONS
- ACTIVATION
- POLYMORPHISMS