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.
Highlights
MAGI1, discovered in 1998 and named BAP1 [1], was initially described as an intracellular adaptor protein involved in stabilizing epithelial junctions [2]
Progress has been made in understanding the role of MAGI1 as tumor suppressor or regulator of vascular functions, there are still many open questions, regarding its regulation in different tissues, and its clinical relevance
One of the outstanding questions relative to MAGI1 function is how it exerts its function as tumor suppressor in different cancers
Summary
MAGI1 (membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1), discovered in 1998 and named BAP1 (brain-specific angiogenesis inhibitor 1associated protein) [1], was initially described as an intracellular adaptor protein involved in stabilizing epithelial junctions [2]. Located on chromosome 3p14.1, MAGI1 is the only known protein in which a GUK domain is combined with five PDZ domains and two WW domains [3] Through these domains, MAGI1 recruits a number of different kinds of molecules to strengthen the junctional complex. MAGI1 is regulated post-transcriptionally by miRNAs, or at the protein level by degradation or phosphorylation. Other mechanisms such as mechanical stress or inflammation regulate MAGI1 expression. We summarize some of the most important findings about MAGI1, in particular concerning its emerging role as vascular regulator and tumor suppressor, along with the mechanisms that regulate its expression. We end up listing a number of open questions that have no clear answers yet, and that we believe deserve further attention
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