Platelet FcγRIIA: An emerging regulator and biomarker in cardiovascular disease and cancer
Qingsong Zhang a); Wenxian Li a); Xin Mao a); Shuo Miao b)
a) Department of Urology, Affiliated Hospital of Qingdao University, Qingdao, China
b) School of Basic Medicine, Qingdao University, Qingdao, China
Abstract
Platelets, anucleate blood cells derive from megakaryocytes, are involved in cardiovascular diseases and tumors. FcγRIIA, the only FcγR expressed on human platelets, is known for its role in immune-related diseases. A growing body of evidence reveals that platelet FcγRIIA is a potential target for the prevention and control of cardiovascular disease and cancer, and is an advantageous biomarker. In this review, we describe the structure and physiological function of platelet FcγRIIA, its regulatory role in cardiovascular disease and cancer, and its potential clinical application.
The structure of FcγRIIA
Platelet FcγRIIA, the Fc receptor for immunoglobulin G (IgG), was first identified as a 40,000-molecular-weight membrane protein shared by monocytes in 1985 [1]. FcγRIIA is the only Fcγ receptor expressed on human platelets, but it is not expressed on mouse platelets. The human FcγRIIA protein is encoded by the FCGR2A gene, which consists of eight exons. The alternative splicing of mRNA allows FCGR2A gene to produce 3 transcripts, two of which encode membrane proteins and the other encode
Ligands of FcγRIIA
FcγRIIA is the receptor for IgG Fc fragment. The polymorphism of FcγRIIA determines the affinity for different IgG subtype [7,8]. Shashidharamurthy R et al. described in detail the binding characteristics of IgG and FcγR and the factors that influence it [9]. In short, H-type FcγRIIA has a higher affinity for human IgG1, IgG2 and IgG3 (IgG3 > IgG1, IgG2 ≫ IgG4), while R-type has a low affinity for human IgG1, IgG2 and IgG3 (IgG3, IgG1 ≫ IgG2 > IgG4). When H-type and R-type are co-expressed on
The signal transduction and functions of FcγRIIA in platelets
Upon ligand recognition and receptor clustering, ligand-induced receptor aggregation results in ITAM phosphorylation by Src, allowing recruitment and activation of Syk. Syk orchestrates the activation of PLCγ2 by regulating the formation of a protein complex that includes scaffolding proteins and signaling molecules. PLCγ2 increases the levels of Ca2+ and DAG, they initiate the activation of Rap1. Rap1 promotes integrin activation, thromboxane A2 generation and granule secretion in platelets [15
The expression of platelet FcγRIIA
The number of FcγRIIA on each platelet ranges from 1000 to 5000 [[22], [23], [24]], which is much smaller than that on monocyte (18,500) or neutrophil (460,000) [25]. In different studies, the content of platelet FcγRIIA in healthy volunteers is significantly different, which may be due to the different detection methods. But there was little variation in platelet expression of FcγRIIA within intra-individuals, the variation was 8.5 % ± 5 % over the course of 1 month in healthy subjects [26].
Thrombosis
FcγRIIA amplifies the activation of platelets in response to stimulus or agonists. Platelet FcγRIIA was identified as a potential risk marker for thrombotic events in circulatory diseases, especially in the setting of shear forces [43]. Compared with their FcγRIIA-negative counterparts, FcγRIIA-positive platelets exhibited increased tyrosine phosphorylation of Syk and PLCγ2 and increased spreading upon interaction with immobilized fibrinogen, and showed markedly enhanced thrombus formation when
Advantages as a biomarker
Increased platelet reactivity was consistently associated with diseases, especially with an increased risk of subsequent cardiovascular events [52,53] and malignant development of tumors [54,55]. Several platelet-derived biomarkers have received a lot of attention, such as GPVI and CD62P, which are membrane receptors expressed on platelets and are up-regulated in response to platelet activation. Their expression levels can be used as independent predictors of cardiovascular events [[56], [57],
Conclusion and future prospects
FcγRIIA, the only Fcγ receptor expressed on human platelets, is abnormally expressed in pathological conditions and is involved in disease progression. FcγRIIA shows unique advantages as a biomarker and target for disease control, especially in cardiovascular disease and cancer. However, there are still some unknowns that need to be further revealed. In the context of cardiovascular disease and tumor, the mechanism of abnormally high expression of FcγRIIA remains unclear. Whether the high…