Is the endogenous ligand for PEAR1 a proteoglycan: clues from the sea

Abstract

Platelet Endothelial Aggregation Receptor 1 (PEAR1) is an orphan receptor of unknown function which mediates powerful activation of platelets and endothelial cells in response to crosslinking by antibodies and sulfated polysaccharides belonging to the dextran and fucoidan families. PEAR1 is a single transmembrane protein composed of 15 epidermal growth factor-like repeat sequences and with a conserved binding motif, YXXM, which when phosphorylated binds to phosphoinositide 3-kinase (PI3K). The 13 th of the repeats has a heparin-binding sequence that is the site of interaction with the sulfated fucoidans and the only known endogenous ligand FcRI. Crosslinking of PEAR1 drives Src family kinase phosphorylation of the cytosolic tail leading to binding and activation of PI3K. In this Opinion Article, we summarise the literature on PEAR1 expression, structure and signalling, and the search for further endogenous ligands. We highlight one article in which phosphorylation of a 150 kDa platelet protein by heparin-containing ligands has been reported and propose that PEAR1 is a receptor for one or more glycosaminoglycan-conjugated proteins (proteoglycans). The up-regulation of PEAR1 at sites of inflammation in the vasculature and its role in angiogenesis suggests a role in the interplay of inflammation, platelets, coagulation and thromboinflammation. We speculate that this may explain the link between single nucleotide variants in PEAR1 and cardiovascular disease.

SVEP1 is an endogenous ligand for the orphan receptor PEAR1

“…Previous studies have reported an interaction between PEAR1 and High affinity immunoglobulin epsilon receptor subunit alpha (FcεRIα) 36 . The differing expression pattern of these two proteins, the inability of monomeric FcεRIα to activate platelets, and the lack of conservation in mouse suggests FcεRIα is not the primary physiological ligand of PEAR1 31 , although pentameric FcεRIα may have a role in PEAR1 signaling 36 . Similarly, the only protein known to interact with SVEP1 is integrin α9β1 55 .…”

“…Antibodies that bind to the extracellular domain (ECD) of PEAR1 (PEAR1ECD) are capable of dimerizing and activating the protein, leading to its association with p85 PI3K and activation of AKT. It is speculated that PEAR1 may be a platelet binding partner 17 , 29 or proteoglycan receptor 31 , but its function in platelets remains poorly understood. In addition, PEAR1 (also known as JEDI or MEGF12) contributes to neoangiogenesis in endothelial cells 32 and glial engulfment 33 – 35 .…”

“…Despite the numerous disease associations of SVEP1 and PEAR1, critical gaps remain in our understanding of the molecular mechanisms of these proteins. For example, the physiological ligand of PEAR1 has yet to be identified despite previous attempts to address this critical question 28 , 31 , 36 , 37 . Defining the disease mechanisms of SVEP1 and PEAR1 will further our understanding of pathophysiology and may generate novel approaches to treat and prevent disease.…”

Experimental validation of computerised models of clustering of platelet glycoprotein receptors that signal via tandem SH2 domain proteins

“…Current antiplatelet drugs such as aspirin and P2Y 12 receptor antagonists target G protein-coupled receptor (GPCR) regulated pathways but are not effective in all individuals and cause a significant increase in risk of bleeding in some people and this can be life-threatening. The glycoprotein receptors GPVI, CLEC-2 and PEAR1 are considered to be targets for a new class of antithrombotic agents based on mouse models and genome-wide association studies with inhibition predicted to cause less bleeding than current antiplatelet agents [ 1 , 2 ]. These receptors are activated by clustering, and antagonists must therefore overcome the net effect of ligand affinity and avidity for effective inhibition, thus favouring inhibitors with high affinity and a slow off-rate of dissociation.…”

“…This includes the GPVI-FcRγ complex and the low affinity immune receptor, FcγRIIA, which signal via an immuno-receptor-tyrosine-based activation motif (ITAM) characterised by two conserved YxxL sequences separated by 6–12 amino acids [ 3 , 4 ]. CLEC-2, on the other hand, signals via a single YxxL known as a hemITAM, and PEAR1 via a single YxxM sequence [ 2 , 5 ]. The binding of the tandem SH2 domains in Syk to phosphorylated ITAM or two hemITAM sequences initiates a signalling cascade that leads to activation of phospholipase C (PLC) γ2.…”