Histone 2B Facilitates Plasminogen-Enhanced Endothelial Migration through Protease-Activated Receptor 1 (PAR1) and Protease-Activated Receptor 2 (PAR2).

Mitali Das,Sujay Subbayya Ithychanda,Edward F Plow

doi:10.3390/biom12020211

Mitali Das, Sujay Subbayya Ithychanda + Show 1 more

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https://doi.org/10.3390/biom12020211

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Journal: Biomolecules	Publication Date: Jan 26, 2022
Citations: 1	License type: CC BY 4.0

Affiliation: Cleveland Clinic Lerner College of Medicine

Abstract

Plasminogen and its multiple receptors have been implicated in the responses of many different cell types. Among these receptors, histone 2B (H2B) has been shown to play a prominent role in macrophage responses. The contribution of H2B to plasminogen-induced endothelial migration, an event relevant to wound healing and angiogenesis, is unknown. Plasminogen enhanced the migration of endothelial cells, which was inhibited by both Protease-Activated Receptor-1 (PAR1) and 2 (PAR2) antagonists. H2B was detected on viable endothelial cells of venous and arterial origin, and an antibody to H2B that blocks plasminogen binding also inhibited the plasminogen-dependent migration by these cells. The antibody blockade was as effective as PAR1 or PAR2 antagonists in inhibiting endothelial cell migration. In pull-down experiments, H2B formed a complex with both PAR1 and PAR2 but not β3 integrin, another receptor implicated in endothelial migration in the presence of plasminogen. H2B was found to be associated with clathrin adapator protein, AP2µ (clathrin AP2µ) and β-arrestin2, which are central to the internationalization/signaling machinery of the PARs. These associations with PAR1-clathrin adaptor AP2µ- and PAR2-β-arrestin2-dependent internalization/signaling pathways provide a mechanism to link plasminogen to responses such as wound healing and angiogenesis.

Highlights

Multiple cell surface molecules serve as plasminogen receptors (PlgRs), and the surfaces of many cells, including monocytoid cells, endothelial cells and tumor cells, are decorated with multiple PlgRs [1–7]
Prior studies have established that PlgRs in general [5,7,44] and Histone 2B (H2B) in particular play roles in inflammatory cell migration [20,45]; its role in endothelial cell migration is totally unknown
Antagonists were resuspended in this same medium. (A) Plg induced significantly higher endothelial cell migration compared to Ut Human umbilical vein endothelial cells (HUVECs), and this increase was significantly inhibited by an irreversible

Summary

Introduction

Multiple cell surface molecules serve as plasminogen receptors (PlgRs), and the surfaces of many cells, including monocytoid cells, endothelial cells and tumor cells, are decorated with multiple PlgRs [1–7] Many of these PlgR bear C-terminal lysines that interact with the lysine binding sites within the kringle domains of Plg. By tethering Plg and plasmin to PlgRs, cells are able to harness the proteolytic activity of plasmin (Plm) to facilitate processes such as migration and invasion. Several of the identified PlgRs lack transmembrane domains and yet are able to induce intracellular signaling responses, such as cytokine production and gene expression [8–11]. In this category of PlgRs, endothelial cell responses have been attributed to Annexin 2 [12–14], p11 [15–17] and Enolase-1 (ENO-1) [6,18]. Concomitant regulation of gene expression in association with these responses has been demonstrated both in vitro and in vivo [10,11]

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