Expression of Human MDGA1 Increases Cell Motility and Cell-Cell Adhesion and Reduces Adhesion to Extracellular Matrix Proteins in MDCK Cells

Abstract

Characterization of the novel human protein MDGA1 (MAM Domain containing Glycosylphosphatidylinositol Anchor-1) has been reported in our laboratory in the past few years. hMDGA1 is a glycoprotein containing 955 aminoacids (137 kDa) attached to the eukaryotic cell membrane by a GPI (Glycosylphosphatidylinositol) anchor and localized specifically into membrane microdomains known as lipid rafts. Moreover, MDGA1 protein contains structural features found in different types of cell adhesion molecules (CAMs) such as the presence of immunoglobulin domains and a MAM domain (Meprin, A5 protein, receptor protein-tyrosine phosphatase μ), suggesting a role of MDGA1 in cell migration and/or adhesion. In order to investigate this aim, stable MDCK cell lines expressing MDGA1 or the truncated proteins IgGPI (lacking the MAM domain) and MAMGPI (lacking Ig domains) were generated. Our results reveal that MDGA1 increases the ability of MDCK cells to migrate, as it contains both Ig and MAM domains which have been implicated in cell motility. In addition, cell adhesion to extracellular matrix proteins, mainly to collagen IV, is reduced by MDGA1 and the IgGPI and MAMGPI truncated proteins. Accordingly, silencing MDGA1 by siRNA revealed a significant increase in adhesion to collagen IV. Furthermore, MDGA1 expression, through the intrinsic properties of the MAM domain, increases cell-cell adhesion independently of the cell monolayer used, suggesting that MDGA1 mediates cell-cell adhesiveness in a heterophilic manner.

Formation of the Cortical Subventricular Zone Requires MDGA1-Mediated Aggregation of Basal Progenitors

“…One possibility is “in trans” binding of MDGA1 to other adhesion proteins of apposing BPs or to components of the extracellular matrix (ECM). Consistent with that, MDGA1 enhances heterophilic cell adhesion to non-MDGA1 expressing cells, as well as to the ECM (Diaz-Lopez et al, 2010). Another possibility is an “in cis” association of MDGA1 with other membrane proteins (Lee et al, 2013, Pettem et al, 2013) to form complexes that generate adhesion between BPs.…”

“…MDGA1 has been shown with in vitro assays to enhance cell adhesion (Diaz-Lopez et al, 2010), a finding consistent with its domain structure and expression patterns, and supporting its proposed function as an IgCAM that has a role in adhesion-based mechanisms of neural development (Litwack et al, 2004, Takeuchi et al, 2007). In vitro studies also indicate that MDGA1 suppresses inhibitory synapse development through its selective association with Neuroligin2 (Lee et al, 2013, Pettem et al, 2013).…”

Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins

“…We speculate that MDGA might have more binding partners besides NL. Indeed, the MDGA1 MAM domain binds a receptor on axons ( Fujimura et al., 2006 ) and enhances cell motility and adhesion to non-MDGA1-expressing cells ( Díaz-López et al., 2010 ). The Ig domains 4–6 are reported to play a role in determining synaptic localization of MDGA1 and MDGA2 ( Loh et al., 2016 ).…”

The Role of HOXB9 and miR-196a in Head and Neck Squamous Cell Carcinoma

“…MAMDC2 is a transmembrane cell adhesion protein of the immunoglobulin superfamily. MAM (meprin/A5-protein/PTPmu) domains are present in numerous proteins with varied functions, with many associated with promotion of cell-cell adhesion [ 56 , 57 ]. Correspondingly, mutations in the MAM domain of the receptor protein tyrosine phosphatase T have been shown to promote cancer cell migration and metastasis in colorectal cancer [ 58 , 59 ].…”