New Concepts and Mechanisms of Platelet Activation Signaling

Brian Estevez, Xiaoping Du, Brian Estevez, Xiaoping Du

Abstract

Upon blood vessel injury, platelets are exposed to adhesive proteins in the vascular wall and soluble agonists, which initiate platelet activation, leading to formation of hemostatic thrombi. Pathological activation of platelets can induce occlusive thrombosis, resulting in ischemic events such as heart attack and stroke, which are leading causes of death globally. Platelet activation requires intracellular signal transduction initiated by platelet receptors for adhesion proteins and soluble agonists. Whereas many platelet activation signaling pathways have been established for many years, significant recent progress reveals much more complex and sophisticated signaling and amplification networks. With the discovery of new receptor signaling pathways and regulatory networks, some of the long-standing concepts of platelet signaling have been challenged. This review provides an overview of the new developments and concepts in platelet activation signaling.

Conflict of interest statement

This work is supported by National Heart, Lung, and Blood Institute Grants and contracts HL-062350, HL-080264, HL-125356, HHSN268201400007C, and HHSN268201700002C (X.D.) and 5F31 HL-123319 (B.E.).

X.D. holds patents relevant to the subject, and has financial interests in DMT, Inc.

©2017 Int. Union Physiol. Sci./Am. Physiol. Soc.

Figures

FIGURE 1.
FIGURE 1.
Signaling pathways of the major platelet receptors for adhesive ligands leading to integrin αIIbβ3 activation and important roles of ITAM pathway sGC, soluble guanylyl cyclase; NOS, NO synthase; SFK, src family kinase; LEC, lymphatic endothelial cell; SLP-76, SH2 domain-containing leukocyte phosphoprotein of 76 kDa; Btk, Bruton's tyrosine kinase; Rap1b, RAS-related protein 1b; MAPKs, mitogen-activated protein kinases; TXA2, thromboxane A2.
FIGURE 2.
FIGURE 2.
Reported signaling pathways of pattern recognition receptors in platelets Note that TLR receptors all require MyD88 for signaling. LPS, lipopolysaccharide; MDP, muramyl dipeptide; HMGB1, high-mobility group box 1; CAP-PE, carboxyalkylpyrrole-phosphatidylethanolamine; TLR, toll-like receptor; PKG, cGMP-dependent protein kinase; RIP2, receptor-interacting protein-2; TIRAP, toll/interleukin-1 receptor domain-containing adapter protein; Myd88, myeloid differentiation factor 88. The question marks represent unknown or hypothesized pathways requiring further investigation.
FIGURE 3.
FIGURE 3.
Synergy among multiple thrombin receptor signaling pathways P115 RhoGEF, p115 Rho guanine nucleotide exchange factor; PKA, cAMP-dependent protein kinase; AC, adenylyl cyclase; Rap1b, RAS-related protein 1b; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; ROS, reactive oxygen species; NOX, NADPH oxidase.
FIGURE 4.
FIGURE 4.
Integrin signaling pathways A: integrin inside-out signaling. A key final step of inside-out signaling is the binding of cytosolic adapter protein talin and kindlins. Question marks indicate that the mechanisms remain unclear and require further investigation. B: early phase integrin outside-in signaling, which requires the interaction between Gα13 and Src with the β3 cytoplasmic domain. Talin dissociation occurs during the early phase outside-in signaling. C: late-phase integrin outside-in signaling, which requires talin reassociation and calpain cleavage of Src binding site in the β3 tail.

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Source: PubMed

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