The Src Family Kinases and Protein Kinase C Synergize to Mediate Gq-dependent Platelet Activation

247

214

Src family kinases (SFKs) play a central role in mediating the rapid response of platelets to vascular injury. They transmit activation signals from a diverse repertoire of platelet surface receptors, including the integrin αIIbβ3, the immunoreceptor tyrosine–based activation motif–containing collagen receptor complex GPVI-FcR γ-chain, and the von Willebrand factor receptor complex GPIb-IX-V, which are essential for thrombus growth and stability. Ligand-mediated clustering of these receptors triggers an increase in SFK activity and downstream tyrosine phosphorylation of enzymes, adaptors, and cytoskeletal proteins that collectively propagate the signal and coordinate platelet activation. A growing body of evidence has established that SFKs also contribute to Gq- and Gi-coupled receptor signaling that synergizes with primary activation signals to maximally activate platelets and render them prothrombotic. Interestingly, SFKs concomitantly activate inhibitory pathways that limit platelet activation and thrombus size. In this review, we discuss past discoveries that laid the foundation for this fundamental area of platelet signal transduction, recent progress in our understanding of the distinct and overlapping functions of SFKs in platelets, and new avenues of research into mechanisms of SFK regulation. We also highlight the thrombotic and hemostatic consequences of targeting platelet SFKs.

Section: Sfks In Gpcr Signalingsupporting

confidence: 66%

Section: Sfks In Gpcr Signalingmentioning

confidence: 99%

Section: Sfks In Gpcr Signalingmentioning

confidence: 99%

See 1 more Smart Citation

Src family kinases: at the forefront of platelet activation

Senis

Mazharian

Mori

2014

247

214

“…After washing, precipitated proteins were analyzed by immunoblotting with the antiphosphotyrosine monoclonal antibody 4G10. 22 …”

Section: Immunoprecipitation and Western Blottingmentioning

confidence: 99%

A critical role for Lyn kinase in strengthening endothelial integrity and barrier function

Han

Zhang

Welch

et al. 2013

Self Cite

“…It was reported that platelet AKT signaling elicited by the binding of agonists to G-protein-coupled receptors is crucial for Ca 21 signaling 33 and that neutrophil AKT2 is critical for Ca 21 mobilization during cell activation. 1 To explain the differential regulation of Ca 21 signaling in platelets and neutrophils by NOX2, we examined the phosphorylation of AKT and MAP kinases ERK and p38.…”

Section: Platelet and Neutrophil Nox2 Differentially Modulate Ca 21 Mmentioning

confidence: 99%

NOX2 is critical for heterotypic neutrophil-platelet interactions during vascular inflammation

Kim¹,

Li²,

Tseng

et al. 2015

Key Points• NOX2-generated ROS regulate the function of surface receptors required for platelet-neutrophil interactions during vascular inflammation.Platelet-leukocyte interactions on activated endothelial cells play an important role during microvascular occlusion under oxidative stress conditions. However, it remains poorly understood how neutrophil-platelet interactions are regulated during vascular inflammation. By using intravital microscopy with mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their bone marrow chimera, we demonstrated that NOX2 from both hematopoietic and endothelial cells is crucial for neutrophil-platelet interactions during tumor necrosis factor alpha-induced venular inflammation. Platelet NOX2-produced reactive oxygen species (ROS) regulated P-selectin exposure upon agonist stimulation and the ligand-binding function of glycoprotein Iba. Furthermore, neutrophil NOX2-generated ROS enhanced the activation and ligand-binding activity of aMb2 integrin following N-formyl-methionyl-leucyl phenylalanine stimulation. Studies with isolated cells and a mouse model of hepatic ischemia/reperfusion injury revealed that NOX2 from both platelets and neutrophils is required for cell-cell interactions, which contribute to the pathology of hepatic ischemia/reperfusion injury. Platelet NOX2 modulated intracellular Ca 21 release but not store-operated Ca 21 entry (SOCE), whereas neutrophil NOX2 was crucial for SOCE but not intracellular Ca 21 release. Different regulation of Ca 21 signaling by platelet and neutrophil NOX2 correlated with differences in the phosphorylation of AKT, ERK, and p38MAPK. Our results indicate that platelet and neutrophil NOX2-produced ROS are critical for the function of surface receptors essential for neutrophil-platelet interactions during vascular inflammation. (Blood. 2015;126(16):1952-1964