title: Disabled-2 modulates homotypic and heterotypic platelet interactions by binding to sulfatides.
abstract: Disabled-2 (Dab2) inhibits platelet aggregation by competing with fibrinogen for binding to the α(IIb) β(3) integrin receptor, an interaction that is modulated by Dab2 binding to sulfatides at the outer leaflet of the platelet plasma membrane. The disaggregatory function of Dab2 has been mapped to its N-terminus phosphotyrosine-binding (N-PTB) domain. Our data show that the surface levels of P-selectin, a platelet transmembrane protein known to bind sulfatides and promote cell-cell interactions, are reduced by Dab2 N-PTB, an event that is reversed in the presence of a mutant form of the protein that is deficient in sulfatide but not in integrin binding. Importantly, Dab2 N-PTB, but not its sulfatide binding-deficient form, was able to prevent sulfatide-induced platelet aggregation when tested under haemodynamic conditions in microfluidic devices at flow rates with shear stress levels corresponding to those found in vein microcirculation. Moreover, the regulatory role of Dab2 N-PTB extends to platelet-leucocyte adhesion and aggregation events, suggesting a multi-target role for Dab2 in haemostasis.
authors.affiliation: Integrated Cellular Responses Laboratory, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Welsh
authors.forename: John J
authors.initials: JJ
authors.lastname: Charonko
authors.forename: Alireza
authors.initials: A
authors.lastname: Salmanzadeh
authors.forename: Karen E
authors.initials: KE
authors.lastname: Drahos
authors.forename: Hadi
authors.initials: H
authors.lastname: Shafiee
authors.forename: Mark A
authors.initials: MA
authors.lastname: Stremler
authors.forename: Rafael V
authors.initials: RV
authors.lastname: Davalos
authors.forename: Daniel G S
authors.initials: DG
authors.lastname: Capelluto
authors.forename: Pavlos P
authors.initials: PP
authors.lastname: Vlachos
authors.forename: Carla V
authors.initials: CV
authors.lastname: Finkielstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D018056:Hemorheology; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D046210:Microfluidic Analytical Techniques; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000502:physiology; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D013433:Sulfoglycosphingolipids / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D019007:P-Selectin; D013433:Sulfoglycosphingolipids; D025521:Tumor Suppressor Proteins