Platelet signaling–A primer

Abstract

Improvements in our understanding of how platelets operate through their signaling networks are critical for diagnosis of unusual primary hemostatic disorders and for rational antithrombotic drug design.

Integrin αIIbβ3 outside-in signaling

“…55,61 Upon ligand binding to a IIb b 3 and integrin clustering, protein phosphatases such as protein-tyrosine phosphatase 1B (PTP-1B) relieve the inhibitory Src phosphorylation, with dissociation of Csk from b 3 , permitting Src activation. 22,55,61 More recent work demonstrates, however, that c-Src associates with b 3 predominantly after platelet activation. 62 Furthermore, an interaction of Ga 13 with an ExE motif in the b 3 -integrin tail has been demonstrated as a key early event required for the activation of c-Src to initiate outside-in signaling, a process Reduced tail-bleeding time.…”

“…17,23 These proteins bind to the b 3 C-terminal tail, to promote domain separation and integrin ectodomain unfolding, converting the integrin to a state capable of high-affinity ligand binding. 17,22 Integrin a IIb b 3 can bind a number of ligands, including fibrinogen, fibrin, von Willebrand factor (VWF), and fibronectin, and ligand binding is influenced by divalent cations. 6,[22][23][24] These ligands contain a common Arg-Gly-Asp (RGD) motif, although a IIb b 3 also interacts with other ligand motifs, with the KQAGDV-containing sequence in the fibrinogen g-chain C terminus being important for platelet aggregation.…”

“…17,22 Integrin a IIb b 3 can bind a number of ligands, including fibrinogen, fibrin, von Willebrand factor (VWF), and fibronectin, and ligand binding is influenced by divalent cations. 6,[22][23][24] These ligands contain a common Arg-Gly-Asp (RGD) motif, although a IIb b 3 also interacts with other ligand motifs, with the KQAGDV-containing sequence in the fibrinogen g-chain C terminus being important for platelet aggregation. [24][25][26][27] Aggregation is mediated by the bridging of fibrinogen between a IIb b 3 on adjacent platelets.…”

“…22,55,74 Syk substrates also include important outside-in effectors, including the Rho guanine nucleotide exchange factors (RhoGEFs) Vav1 and Vav3, and the SH2-containing leukocyte protein of 76 kDa (SLP-76). 55,75 The comparable phenotypes of mice lacking such proteins reflect their interconnected roles downstream of a IIb b 3 (Figure 2).…”

“…18,19 In resting platelets, integrin a IIb b 3 is maintained in a low-affinity state, in which the ectodomain exists in a closed conformation ( Figure 1A). [20][21][22] Inside-out signaling to integrins from various activated platelet receptors for soluble ligands (eg, P 2 Y 12 , protease-activated receptors [PAR]) or extracellular matrix components (eg, GPIb-IX-V, GPVI) triggers pathways commonly converging on the activation of the small GTPase, Rap1, and the recruitment of the four-point-one, ezrin, radixin, moesin (FERM) domain-containing proteins talin and kindlin. 17,23 These proteins bind to the b 3 C-terminal tail, to promote domain separation and integrin ectodomain unfolding, converting the integrin to a state capable of high-affinity ligand binding.…”