MAGI1, a Scaffold Protein with Tumor Suppressive and Vascular Functions

Abstract

MAGI1 is a cytoplasmic scaffolding protein initially identified as a component of cell-to-cell contacts stabilizing cadherin-mediated cell–cell adhesion in epithelial and endothelial cells. Clinical-pathological and experimental evidence indicates that MAGI1 expression is decreased in some inflammatory diseases, and also in several cancers, including hepatocellular carcinoma, colorectal, cervical, breast, brain, and gastric cancers and appears to act as a tumor suppressor, modulating the activity of oncogenic pathways such as the PI3K/AKT and the Wnt/β-catenin pathways. Genomic mutations and other mechanisms such as mechanical stress or inflammation have been described to regulate MAGI1 expression. Intriguingly, in breast and colorectal cancers, MAGI1 expression is induced by non-steroidal anti-inflammatory drugs (NSAIDs), suggesting a role in mediating the tumor suppressive activity of NSAIDs. More recently, MAGI1 was found to localize at mature focal adhesion and to regulate integrin-mediated adhesion and signaling in endothelial cells. Here, we review MAGI1′s role as scaffolding protein, recent developments in the understanding of MAGI1 function as tumor suppressor gene, its role in endothelial cells and its implication in cancer and vascular biology. We also discuss outstanding questions about its regulation and potential translational implications in oncology.

Low-Dose Anti-HIV Drug Efavirenz Mitigates Retinal Vascular Lesions in a Mouse Model of Alzheimer’s Disease

“…Magi1 encodes a membrane-associated guanylate kinase, also known as brain-specific angiogenesis inhibitor 1-associated protein. MAGI1 is a scaffold protein, which interacts with various proteins and thereby is involved in multiple cell functions including regulation of angiogenesis, vascular integrity, and permeability as well as cell–cell and cell–matrix adhesion ( Wörthmüller and Rüegg, 2021 ). Gpr126 encodes adhesion G-protein coupled receptor G6, which is highly enriched in vascular endothelial cells.…”

Dynamic, but Not Necessarily Disordered, Human-Virus Interactions Mediated through SLiMs in Viral Proteins

“…Dlg, a Drosophila discs large protein and a protein with 3 PDZ domains, is one of the scribble complex proteins, which are involved in maintaining the cellular polarity and adhesion at the cellular junction [87]. MAGI-1 is a membrane associated guanylate cyclase that is located in cellular junction and is important for regulating the proliferation and cellular adhesion between cells [88]. Dlg and MAGI-1 function in tumor suppression [85,87,88].…”

“…MAGI-1 is a membrane associated guanylate cyclase that is located in cellular junction and is important for regulating the proliferation and cellular adhesion between cells [88]. Dlg and MAGI-1 function in tumor suppression [85,87,88]. The binding of human adenovirus 9 to these human proteins inhibits their function through sequestration.…”

A New Story of the Three Magi: Scaffolding Proteins and lncRNA Suppressors of Cancer

“…As shown in Table 1 and Figure 2 , MAGI proteins interact with a wide variety of effector proteins involved in the control of cell proliferation, apoptosis, or cell motility. Although not all of these interactions have so far been linked to MAGI antitumor activity (e.g., MAPK, Notch, Rho, Smad), some of them are clearly established ( Figure 3 ) [ 164 , 165 , 166 ].…”

“…As far as MAGI1 is wild-type, its accumulation could be raised by Cox2 inhibitors leading to increased PTEN stability and activity. In this connection, the regulation of endothelial cell activity, and the tuning of vascular permeability and angiogenesis by MAGI1 might constitute another level to control carcinogenesis [ 166 ]. Growing and promising efforts are devoted to evaluating the druggability of PDZ domains [ 7 , 8 ].…”