Platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling and vascular integrity

Abstract

Platelets are well-known for their critical role in hemostasis, that is, the prevention of blood loss at sites of mechanical vessel injury. Inappropriate platelet activation and adhesion, however, can lead to thrombotic complications, such as myocardial infarction and stroke. To fulfill its role in hemostasis, the platelet is equipped with various G protein-coupled receptors that mediate the response to soluble agonists such as thrombin, ADP, and thromboxane A2. In addition to G protein-coupled receptors, platelets express 3 glycoproteins that belong to the family of immunoreceptor tyrosine-based activation motif receptors: Fc receptor γ chain, which is noncovalently associated with the glycoprotein VI collagen receptor, C-type lectin 2, the receptor for podoplanin, and Fc receptor γII A, a low-affinity receptor for immune complexes. Although both genetic and chemical approaches have documented a critical role for platelet G protein-coupled receptors in hemostasis, the contribution of immunoreceptor tyrosine-based activation motif receptors to this process is less defined. Studies performed during the past decade, however, have identified new roles for platelet immunoreceptor tyrosine-based activation motif signaling in vascular integrity in utero and at sites of inflammation. The purpose of this review is to summarize recent findings on how platelet immunoreceptor tyrosine-based activation motif signaling controls vascular integrity, both in the presence and absence of mechanical injury.

Keywords: blood and lymphatic vessels; blood platelets; hemostasis; inflammation.

Figure 1. Platelet-dependent hemostasis after vascular injury and at sites of inflammation

Schematic representation of important molecular mechanisms regulating platelet-dependent hemostasis. At sites of vascular injury, platelet activation and adhesion is strongly dependent on soluble agonists and their respective G protein-coupled receptors (GPCRs) expressed on the platelet surface. Engagement of GPCRs leads to the rapid activation of phospholipase (PL)Cβ2 and PI3 kinase, events that are critical for the activation of the small GTPase Rap1, affinity regulation in platelet integrins, and platelet aggregate formation. The contribution of immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors to platelet activation at sites of vascular injury is weak when compared to GPCRs. In contrast, hemostasis at sites of inflammation depends primarily on platelet ITAM signaling and is independent of major platelet adhesion receptors. These findings suggest a model where platelets get activated under low/no flow conditions in the extravascular space, leading to the release of soluble factors that secure vascular integrity. Both the signaling response downstream of PLCγ2 and the platelet-derived mediator(s) critical for vascular integrity in inflammation are currently unknown. PAR: protease activated receptor; TxA₂: thromboxane A₂; TP: TxA₂ receptor; FcRγ: Fc receptor γ-chain; CLEC2: C-type lectin 2; PDPN: podoplanin; PI3K: PI3 kinase; PLC: phospholipase C; ECM: extracellular matrix