Anthrax toxin receptor 2 functions in ECM homeostasis of the murine reproductive tract and promotes MMP activity.

Claire V Reeves,Jan K Kitajewski,Pelisa C Charles-Horvath,Valeriya Y Borisenko,Joy Y Vink,John A T Young,Xing Wang,F Gisou Van Der Goot

doi:10.1371/journal.pone.0034862

Claire V Reeves, Jan K Kitajewski + Show 6 more

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https://doi.org/10.1371/journal.pone.0034862

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Abstract

Anthrax Toxin Receptor proteins function as receptors for anthrax toxin, however physiological activity remains unclear. To evaluate the biological role of Antxr2, we generated Antxr2−/− mice. Antxr2−/− mice were viable, however Antxr2 is required for parturition in young females and for preserving fertility in older female mice. Histological analysis of the uterus and cervix revealed aberrant deposition of extracellular matrix proteins such as type I collagen, type VI collagen and fibronectin. A marked disruption of both the circular and longitudinal myometrial cell layers was evident in Antxr2−/− mice. These changes progressed as the mice aged, resulting in a thickened, collagen dense, acellular stroma and the disappearance of normal uterine architecture. To investigate the molecular mechanism underlying the uterine fibrosis we performed immunoblotting for MMP2 using uterine lysates and zymography using conditioned medium from Antxr2−/− mouse embryonic fibroblasts and found reduced levels of activated MMP2 in both. This prompted us to investigate MT1-MMP status, as MMP2 processing is regulated by MT1-MMP. We found MT1-MMP activity, as measured by MMP2 processing and activation, was enhanced by expression of either ANTXR1 or ANTXR2. We identified an ANTXR2/MT1-MMP complex and demonstrated that MT1-MMP activity is dependent on ANTXR2 expression levels in cells. Thus, we have discovered that ANTXR1 and ANTXR2 function as positive regulators of MT1-MMP activity.

Highlights

The Anthrax Toxin Receptor (ANTXR) proteins, ANTXR1 and ANTXR2, are cellular receptors that contain a von Willebrand factor type A domain, a transmembrane domain and a cytosolic tail with putative signaling motifs. vWF domains are known to facilitate protein-protein interactions when found on extracellular matrix (ECM) constituents or cell adhesion proteins like /-integrin subunits [1] and constitute ligand binding sites on ANTXRs [2]
Antxr22/2 Mice Exhibit a Failure in Parturition To ascertain the function of Antxr2, we generated a conditional
Antxr22/2 mice were viable at birth and developed normally, showing no striking phenotypic difference when compared with their wild type and heterozygous littermates at the macroscopic level

Summary

Introduction

The Anthrax Toxin Receptor (ANTXR) proteins, ANTXR1 and ANTXR2, are cellular receptors that contain a von Willebrand factor type A (vWF) domain, a transmembrane domain and a cytosolic tail with putative signaling motifs. vWF domains are known to facilitate protein-protein interactions when found on extracellular matrix (ECM) constituents or cell adhesion proteins like /-integrin subunits [1] and constitute ligand binding sites on ANTXRs [2]. VWF domains are known to facilitate protein-protein interactions when found on extracellular matrix (ECM) constituents or cell adhesion proteins like /-integrin subunits [1] and constitute ligand binding sites on ANTXRs [2]. Both ANTXR1 and ANTXR2 have been demonstrated to interact with ECM proteins in vitro [3,4,5]. ANTXR1 has been demonstrated to be important for endothelial cell migration and network formation [4,7] Despite these studies, the physiological function of the ANTXR proteins remains to be fully elucidated

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