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Integrins are αβ heterodimeric cell surface receptors that play an important role in cell physiology by regulating cell adhesion and cell migration. In human platelets, integrin αIIbβ3 promotes platelet aggregation and thrombus formation at sites of blood vessel injury to prevent blood loss, while the genetic defect of platelet integrin αIIbβ3 in patients with Glanzmann's thrombasthenia causes a severe bleeding disorder. Under various pathological conditions, platelets can spontaneously form aggregates and cause thrombotic disorders.
Integrins function as allosteric bidirectional signaling receptors that not only provide a link between the extracellular matrix and the cell cytoskeleton, but also initiate intracellular signaling cascades. During platelet aggregation, integrin αIIbβ3 switches from a low to a high affinity receptor for fibrinogen (inside-out signaling), and fibrinogen binding to the activated receptor in turn stimulates outside-in signaling leading to the interaction of the integrin β subunit cytoplasmic tail with intracellular proteins including cytoskeletal proteins, protein kinases as well as adaptor proteins.
Our research focuses on two of the β3 integrin intracellular ligands, the cytoskeletal protein talin and the protein kinase Src. Talin has 2 integrin contact sites and provides a direct link between the integrin β subunit and actin filaments of the cytoskeleton, while Src is required to phosphorylate the β3 cytoplasmic tail as well as other downstream partners. Our objective is to set up a mouse model allowing the in vivo investigation of the involvement of Src and talin in platelet αIIbβ3 outside-in signaling. If successful, this animal model will also allow high throughput in vivo analysis of patient-derived or lab-designed integrin mutants for structure-function studies, as the functional properties of these mutant receptors can be directly explored not only in a physiological relevant platelet but also megakaryocyte environment. In addition, understanding the molecular mechanisms underlying these protein-protein interactions will open up the way to novel therapeutic approaches to block selectively integrin inside-out or outside-in signaling applicable to various prothrombotic pathologies.
