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

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.

Proteomic Changes in the Hippocampus after Repeated Explosive-Driven Blasts

“…It is indeed intriguing that MAGI3, a protein principally studied in the context of cancer mechanisms, , was up-regulated in the Hippo of 2xBl vs SH rats. MAGI3 is known to interact with a number of important signaling cascades, including ERK, AKT, WNT, and JNK pathways, with possible roles in DNA-repair pathways, cell-to-cell junction interactions, and angiogenesis . MAGI3, while it has never been reported in explosive-driven blast studies before, represents actually an important scaffolding protein that belongs to the widely expressed MAGI protein family, with MAGI1 and MAGI3 being ubiquitous, and MAGI2 expressed in the brain and kidney tissues.…”

“…MAGI3 together with PTEN modulates the kinase activity of AKT1. Also, MAGI3 interactions with PTPRB and phosphorylated tyrosine suggests that it may link receptor tyrosine phosphatase with its substrates at the plasma membrane …”

Phosphorylation-dependent recognition of diverse protein targets by the cryptic GK domain of MAGI MAGUKs

“…MAGIs play essential roles in a broad spectrum of biological processes including cell polarity, cell adhesion, cell migration, synaptic development, and signaling, among others (4,8,9). Aberrations in MAGIs contribute to various human diseases, ranging from neurological diseases to cancers (10)(11)(12). Among the three paralogs of MAGIs, MAGI1 and MAGI3 are ubiquitously expressed, whereas MAGI2 is mainly expressed in neuronal synapses and kidney podocytes (10).…”

“…Aberrations in MAGIs contribute to various human diseases, ranging from neurological diseases to cancers (10)(11)(12). Among the three paralogs of MAGIs, MAGI1 and MAGI3 are ubiquitously expressed, whereas MAGI2 is mainly expressed in neuronal synapses and kidney podocytes (10). There are three alternative splicing variants of the MAGI2 gene: MAGI2α, MAGI2β, and MAGI2γ.…”

MAGIs: Junctional Scaffolds Linking Inter-Cellular Junction Architecture, Actin Cytoskeleton Dynamics, and Signaling Pathways

“…In different cancer cell lines, junctional MAGI scaffolds have indeed been shown to control several signaling pathways. Although the pathways identified are diverse (for a recent and exhaustive review see [22]), it is possible that the underlying cause for signaling pathway modulation by MAGIs could be linked to their role as actin dynamics' regulators (Figure 1).…”