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

SIMPLE SUMMARY: MAGI1, 2, and 3 belong to a subgroup of the MAGUK family of scaffolding proteins, and are comprised of 6 PDZ domains, 2 WW domains, and 1 GUK domain. MAGIs associate with cell surface receptors, junctional complexes, and interact selectively with a wide range of effectors, including the PTEN tumor suppressor, the β-catenin, and YAP1 proto-oncogenes. The regulation of the PI3K/AKT, the Wnt, and the Hippo signaling pathways, on the one hand, the downmodulation of MAGIs in various types of cancers, and its physiopathological significance, on the other, make these scaffolding proteins considered to be tumor suppressors. Interestingly, MAGI1 and MAGI2 genetic loci generate a series of long non-coding RNAs (lncRNAs) that act as promoters or suppressors of tumors in a tissue-dependent manner by sponging some sets of miRNAs or by regulating epigenetic processes. This review details current knowledge of paths followed by the three MAGIs to control carcinogenesis. ABSTRACT: Scaffolding molecules exert a critical role in orchestrating cellular response through the spatiotemporal assembly of effector proteins as signalosomes. By increasing the efficiency and selectivity of intracellular signaling, these molecules can exert (anti/pro)oncogenic activities. As an archetype of scaffolding proteins with tumor suppressor property, the present review focuses on MAGI1, 2, and 3 (membrane-associated guanylate kinase inverted), a subgroup of the MAGUK protein family, that mediate networks involving receptors, junctional complexes, signaling molecules, and the cytoskeleton. MAGI1, 2, and 3 are comprised of 6 PDZ domains, 2 WW domains, and 1 GUK domain. These 9 protein binding modules allow selective interactions with a wide range of effectors, including the PTEN tumor suppressor, the β-catenin and YAP1 proto-oncogenes, and the regulation of the PI3K/AKT, the Wnt, and the Hippo signaling pathways. The frequent downmodulation of MAGIs in various human malignancies makes these scaffolding molecules and their ligands putative therapeutic targets. Interestingly, MAGI1 and MAGI2 genetic loci generate a series of long non-coding RNAs that act as a tumor promoter or suppressor in a tissue-dependent manner, by selectively sponging some miRNAs or by regulating epigenetic processes. Here, we discuss the different paths followed by the three MAGIs to control carcinogenesis.