Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 2, Pages 325-330Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1710828115
Keywords
platelets; integrin; mechanobiology; molecular tension sensors
Categories
Funding
- National Science Foundation [ECCS-1542174]
- National Institutes of Health [R01GM124472, R01HL121264, R01HL130918, U01HL117721, U54HL112309, R21HL130818]
- National Science Foundation CAREER Awards [1150235, 1553344]
- NSF Graduate Research Fellowship Program [1444932]
- National Cancer Institute Predoctoral to Postdoctoral Fellow Transition Award [F99CA223074]
- National Science Foundation Graduate Research Fellowship Program [1444932]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1553344] Funding Source: National Science Foundation
- Direct For Education and Human Resources
- Division Of Graduate Education [1444932] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1350829] Funding Source: National Science Foundation
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Platelet aggregation at the site of vascular injury is essential in clotting. During this process, platelets are bridged by soluble fibrinogen that binds surface integrin receptors. One mystery in the mechanism of platelet aggregation pertains to how resting platelets ignore soluble fibrinogen, the third most abundant protein in the bloodstream, and yet avidly bind immobile fibrinogen on the surface of other platelets at the primary injury site. We speculate that platelet integrins are mechanosensors that test their ligands across the platelet-platelet synapse. To investigate this model, we interrogate human platelets using approaches that include the supported lipid bilayer platform as well as DNA tension sensor technologies. Experiments suggest that platelet integrins require lateral forces to mediate platelet-platelet interactions. Mechanically labile ligands dampen platelet activation, and the onset of piconewton integrin tension coincides with calcium flux. Activated platelets display immobilized fibrinogen on their surface, thus mediating further recruitment of resting platelets. The distribution of integrin tension was shown to be spatially regulated through two myosin-signaling pathways, myosin light chain kinase and Rho-associated kinase. Finally, we discovered that the termination of integrin tension is coupled with the exposure of phosphatidylserine. Our work reveals the highest spatial and temporal resolution maps of platelet integrin mechanics and its role in platelet aggregation, suggesting that platelets are physical substrates for one another that establish mechanical feedback loops of activation. The results are reminiscent of mechanical regulation of the T-cell receptor, E-cadherin, and Notch pathways, suggesting a common feature for signaling at cell junctions.
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