A New Story of the Three Magi: Scaffolding Proteins and lncRNA Suppressors of Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Implication of MAGI Molecular Scaffolds in the Control of Carcinogenesis
2.1. MAGI Structure
2.2. MAGI Molecular Partners
2.3. MAGIs in Cancer
2.3.1. Genetic Alteration, Silencing
2.3.2. MAGIs Expression and Prognosis
2.3.3. Signaling Pathways and Effector Systems Involved in the Tumor Suppressor Activities of MAGIs
PTEN/PI3K/AKT Signaling Pathway
Beta-Catenin/Wnt Signaling Pathways
HIPPO Signaling Pathway
Junctional Complex Stabilizer, Invasion Suppressor Activity
Competitions between Scaffolding Molecules and Molecular Partners
3. MAGI ceRNAs in Carcinogenesis
4. Conclusions, Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Molecular Partners | Full Name | Function | MAGI1 | Interaction MAGI2 | MAGI3 | MAGI Binding Domain * | Biological Impact | References |
---|---|---|---|---|---|---|---|---|
Receptor Ligands, Membrane Receptors, Cell Adhesion Molecules | ||||||||
ADAM17; TACE | Disintegrin and metalloproteinase domain-containing protein 17; ADAM17, | Membrane-anchored metalloproteinase | + | ND | ND | PDZ2 | Involved (with ɣ-secretase) in coxsackie virus and adenovirus receptor (CAR Ex8) | [48] |
ADGRB1; BAI1 | Adhesion G protein-coupled receptor B1; Brain-specific angiogenesis inhibitor-1 | G-protein-coupled receptor involved in inflammation, tumorigenesis, and phagocytosis. Mobilizes Rho signaling pathway through Gα12/13 and Rac1 pathways via ELMO/DOCK GEF. | + | + | + | PDZ4 | BAI1 PDZ-binding motif required for Rho signaling, association with β-Arrestin2, and receptor ubiquitination. MAGI3 potentiates ERK signaling by a constitutively active BAI1. MAGI1 was originally designed BAI1-associated protein 1 | [43,49] |
ADRB1 | Beta-1 adrenergic receptor (β1AR); Adrenoceptor beta 1; | G protein-coupled receptor (GPCR), a receptor for epinephrine and norepinephrine | + | + | + | PDZ1 (MAGI1, 3); PDZ1 and PDZ2 (MAGI2) | Interaction MAGI2/ β1AR enhanced by agonist stimulation. MAGI2 increases agonist-induced β1AR internalization. Ternary complex involves MAGI2/ β1AR/ β-catenin. MAGI3 impairs β1AR-mediated ERK1/2 activation but has no effect on cAMP generation or β1AR internalization | [50,51] |
ADRB2 | Beta-2 adrenergic receptor (β2AR) | G protein-coupled receptor (GPCR) | ND | ND | + | PDZ5 | Agonist stimulation of β2AR promotes MAGI3/ β2AR interaction (dependent on β2AR phosphorylation by GRK). MAGI3 inhibits β2AR-mediated ERK activation. | [52] |
ActRIIA | Activin A receptor type 2A | Ser/Thr kinase, a component of the heterodimeric receptor for activin, a member of the TGFβ family | ND | + | ND | PDZ5 | MAGI2 interacts with activin type 2 receptor via its PDZ5 and with SMAD3 via its WW domains. MAGI2 negatively regulates activin/ SMAD3 -induced gene transcription | [53] |
CACNG2; Stargazin | Voltage-dependent calcium channel gamma-2 subunit; Stargazin | Type I transmembrane AMPA receptor regulatory protein. Promotes targeting of AMPA-selective glutamate receptors; Modulates their gating properties. | ND | + | + | PDZ1, PDZ3, and PDZ5 | Stargazin recruits MAGI2 to cell membranes and cell–cell contact. MAGI2 might act as a physical link between AMPAR/ AMPAR regulators complexes and synaptic adherens junctions | [54] |
CTNNB1 | Catenin beta 1; Beta-catenin | Component of the protein complex that constitutes adherens junctions, involved in cadherin-mediated cell–cell contact and tissue integrity. Effector system of the canonical Wnt signaling pathway: coactivator for the TCF/LEF family of transcription factors and Wnt target genes (Cyclin D1, c-Myc, MMP7). | + | + | + | PDZ5 | MAGIs are recruited to cadherin junctional complexes by PDZ5 binding to β-catenin. The interaction of PTEN with MAGI PDZ2 allows the tuning of PtdIns(3,4,5)P3 and downstream effectors with PH domain (e.g., AKT, RhoGEF) stabilizing junctional complexes and inhibiting invasiveness. MAGIs also restrain β-catenin nuclear translocation and Wnt target genes transactivation | [20,21,22,35,36,37,55,56] |
CTNND2; NPRAP | Catenin delta 2; Delta-catenin | Member of the armadillo protein family, involved in cell–cell contacts and signal transduction | ND | + | ND | PDZ5 | Junctional organization | [57] |
CDH23 | Cadherin-23 | Member of the cadherin superfamily; Involved in the organization of the stereocilia bundle of hair cells in the cochlea | + | − | − | PDZ4 | MAGI1, PIST, and harmonin collaborate in intracellular trafficking and plasma membrane targeting of cadherin 23 | [58,59] |
CRHR1; CRFR1 | Corticotropin-releasing hormone receptor 1; | G-protein (Gα) coupled receptor, binds neuropeptides of the corticotropin-releasing hormone family | + | + | + | PDZ1 | Receptor clustering; MAGIs regulate CRFR1 internalization by mediating β-arrestin recruitment. MAGI modulate CRFR1 signaling via the MAPK pathway but not cAMP formation | [60,61,62] |
CXADR; CAR | Coxsackievirus and adenovirus receptor | Component of epithelial apical junction complexes, a membrane receptor for group B coxsackieviruses, and subgroup C adenoviruses. Isoforms originate from alternative splicing, e.g., CAR Ex8 | + | ND | ND | PDZ1 and PDZ3 | CAR Ex8 localizes to the apical surface of epithelial cells. Interaction with MAGI1 PDZ1 protects CAR Ex8 from degradation, whereas MAGI PDZ3 interaction triggers CAR Ex8 cleavage by ADAM17. | [48] |
DLL1 | Delta-like protein; Delta1 | Involved in cell–cell communication. Delta proteins activate Notch through their extracellular domains; the intracellular domains also exert biological functions. | + | + | + | PDZ4 | MAGI1 recruits Delta1 to adherens junctions through its interaction with β-catenin. In Zebrafish, MAGI1, 2, and 3 interact with Delta1 and control neuron migration | [63,64,65] |
ERBB4; HER4 | Receptor tyrosine-protein kinase erbB-4 | Member of EGF receptor family tyrosine kinases. Binds to and is activated by neuregulins. Mutated in various cancer types | + | + | ND | PDZ1 | MAGI1, 2 bind ERBB4 and R-PTP-zeta, and form a ternary phosphotyrosine kinase/ phosphotyrosine phosphatase complex. Bring ERBB4 and R-PTP-zeta to specific cellular domains. ERBB4 phosphorylation of MAGI enhanced by ERB4 ligand. | [66] |
FZD4 | Frizzled 4, Fz-4 | Receptor for Wnt proteins; Activates disheveled proteins leading to nuclear accumulation of β-catenin and transactivation of Wnt target genes | + | ND | + | PDZ1 | MAGI3 forms a ternary complex with Fz-4 and VANGL2 (involved in planar cell polarity) at cell–cell contact. Both Fz-4 and Vangl2 interact with MAGI3 PDZ1suggesting MAGI3 oligomerization. This ternary complex activates JNK via Rac1 | [67,68,69] |
GRIN2A; NMDAR2A; NR2A | Glutamate receptor ionotropic, NMDA 2A | Component of NMDA receptor complexes, ligand-gated ion channels with high calcium permeability, and voltage-dependent sensitivity to magnesium. | ND | + | ND | PDZ5 | Clustering of NMDA receptors? Required for NMDA receptor-induced RhoA. Hampered NMDA 2 internalization. | [30,70,71] |
HTR2A | 5-Hydroxytryptamine receptor 2A | One of the receptors for serotonin (this also binds mescaline and LSD psychoactive substances); Gq/G11-protein-coupled, increases cellular levels of IP3 and DAG via PLC and modulates PKC activity and Ca2+ release from intracellular stores | + | + | + | PDZ nd | MAGIs differentially regulate 5-HT2AR activity: MAGI1, 3 favor receptor internalization; MAGI2, 3 enhance receptor trafficking. MAGIs increase PLC-β3 recruitment to the receptor and IP3 formation. MAGI knockdown increases ERK1/2 activation by 5-HT-2A, independently of the PDZ binding motif | [72] |
IGSF5; JAM4 | Immunoglobulin superfamily member 5; Junctional adhesion molecule 4 | Cell adhesion molecule at tight junctions of kidney glomerulus and small intestinal epithelial cells. Mediates calcium-independent homophilic adhesion. | + | ND | ND | PDZ1 and PDZ4 | MAGI1 induces clustering of IgSF5 and strengthens cell adhesion. May regulate the permeability of kidney glomerulus and small intestinal epithelium | [73] |
LRP2; Megalin | Low-density lipoprotein receptor-related protein 2; Megalin | Endocytic receptor expressed in absorptive epithelial tissues. Involved in reuptake of sterols, lipoproteins, vitamin-binding proteins, and hormones | + | ND | ND | PDZ5 | [23] | |
LPAR2; LPA2 receptor | Lysophosphatidic acid receptor 2 | G protein (Gi/Go, G12/G13, & Gq)-coupled receptor. Involved in phospholipase C-beta (PLC-β) signaling pathway | − | + | + | PDZ5 | MAGI3 inhibits NHERF2 –induced migration and invasion of colon cancer cells by competing with NHERF2 for binding to LPAR2 and its downstream effector PLC-β3, leading to decreased NFkB and JNK activities | [74,75] |
NGFR; TNFRSF16; P75NTR | Tumor necrosis factor receptor superfamily member 16; NGF receptor | Low-affinity receptor for neurotrophins (NGF, BDNF, NTF3, and NTF4). Mediates RhoA-dependent inhibition of growth of regenerating axons. | + | − | − | PDZ0 | MAGI1 interacts with NGF-R and SHC, positive regulation of NGF-stimulated SHC-ERK pathway | [28] |
NLGN1 | Neuroligin-1 | Neuronal cell surface protein. Transsynaptic adhesion molecules. Role in synapse function and synaptic signal transmission. | + | + | + | PDZ1 | S-SCAM (MAGI2) is tethered by β-catenin and triggers the accumulation of neuroligin, which subsequently recruits PSD-95 to synapses | [30,76,77] |
NPHS1; Nephrin | Nephrin; Renal glomerulus-specific cell adhesion receptor | Transmembrane protein, member of the immunoglobulin family of cell adhesion molecules. Involved in glomerular filtration barrier in the kidney (slit diaphragm of glomerular podocytes) | + | + | - | PDZ3 (MAGI1); Indirect or PDZ3-5 (MAGI2) | In podocytes, MAGI1 connects Nephrin and JAM4 to the actin cytoskeleton, critical for stable assembly of the slit diaphragm. Nephrin/ MAGI1 interaction enhances Rap1 activation, essential for maintaining slit diaphragm function. | [78,79,80,81,82] |
PTPRZ1; RPTPB; RPTPbeta | Receptor-type tyrosine-protein phosphatase zeta; R-PTP-zeta | Role in cell adhesion, neurite growth, and neuronal differentiation, blood vessel remodeling, and angiogenesis | + | + | + | PDZ2 | Favors interactions of R-PTP-zeta with its substrates at the plasma membrane. MAGI1, 2 form a ternary phosphotyrosine kinase/ phosphotyrosine phosphatase complex with ERBB4 and R-PTP-zeta. R-PTP-zeta dephosphorylates Tyr-373 and Tyr-858 of MAGI1 | [66,83,84] |
SDK1; Sidekick-1 | Protein sidekick-1 | Transmembrane protein, immunoglobulin family of cell adhesion molecules; promotes synaptic connectivity via homophilic interactions | + | + | ND | WW and PDZ4 and/or PDZ5; PDZ2 and/or PDZ3 | Localizes Sidekick1, 2 in distinct subsets of retinal synapses. Upregulation of Sidekick during focal segmental glomerulosclerosis impairs MAGI1 function, promotes actin cytoskeleton disruption, leading to podocyte dysfunction | [27,85] |
TGFA; TGF-alpha | Protransforming growth factor alpha | Growth factor; ligand for EGFR; acts as transmembrane-bound or a soluble ligand | − | + | + | PDZ1 | Role in the trafficking of TGF-alpha to the cell surface in polarized epithelial cells | [33] |
VANGL2, LTAP | Vang-like protein 2 (Vangl2); Loop-tail-associated protein (LTAP) | Membrane protein; Involved in regulation of planar cell polarity (non-canonical Wnt signaling pathway) | ND | + | + | PDZ1 | MAGI3 forms a ternary complex with Fz-4 and Vangl2 at cell–cell contact and activates JNK via Rac1. Both Fz-4 and Vangl2 interact with MAGI3 PDZ1 suggesting MAGI3 oligomerization. In podocytes, MAGI2 forms a ternary complex with nephrin and Vangl2 | [68,86] |
VIPR1; VPAC1 | Vasoactive intestinal polypeptide receptor 1; VIP-R-1 | G protein-coupled receptor; receptor for vasoactive intestinal peptide, involved in smooth muscle relaxation, exocrine and endocrine secretion, and hydro-electrolytic flux | ND | + | ND | PDZ1 and/or PDZ2 | MAGI2 reduces VIP-R-1 activation, leading to decreased receptor internalization (GRK dependent). Recruitment of VIP-R-1 close to CFTR enables localized cAMP generation and hydroelectrolytic secretion with a minimal cellular response. | [87] |
Adaptors, Scaffolding Molecules | ||||||||
AMOTL2 | Angiomotin-like protein 2 | Member of the angiomotin membrane-associated scaffold proteins. Involved in cadherin linkage to the cytoskeleton and in YAP1 signaling | + | ND | ND | 2nd WW | MAGI1 downregulation is associated with enhanced accumulation of AMOTL2 and E-cadherin in MCF7 cells. Junctional dysfunction and cytoskeletal tension might activate the p38 stress pathway and tumorigenesis | [88] |
ARRB2; BAAR2 | Arrestin beta 2; Beta-arrestin-2 | Member of arrestin protein family; scaffolding molecule; involved in agonist-mediated desensitization of GPCR, and in signaling regulation, e.g., TGFβ, MAPK, PTEN, AKT, NFkB, TP53 | + | ND | ND | PDZ nd | Role in regulating β-arrestin-2 recruitment to CRFR1 and receptor signaling. Involved in receptor/β-arrestin complex stability and trafficking, and in signaling functions of receptors. | [61,62] |
Axin | Axin | Tumor suppressor involved in the control of Wnt pathway. Cytoplasmic protein interacting with APC, β-catenin, GSK 3β, PP 2A, and itself. Component of the complexities involved in β-catenin destruction. | ND | + | ND | GuK | MAGI2 forms a complex with β-catenin and Axin and competes with GSK3β for Axin-binding. MAGI2 may protect β-catenin from degradation by inhibiting its phosphorylation by GSK3β. | [89] |
DLGAP4; SAPAP4 | Disks large-associated protein 4 | Membrane-associated guanylate kinase found at the postsynaptic density in neuronal cells | ND | + | ND | GuK | Interaction of DLGAP with MAGI2 (S-SCAM) | [30] |
DLG4; SAP-90; PSD95 | Disks large homolog 4; Synapse-associated protein 90; Post-synaptic density protein 95 | MAGUK family, contains 1 domain SH3, 1 Guk domain, and 3 PDZ domains. Postsynaptic scaffolding protein involved in synaptogenesis and synaptic plasticity | ND | + | ND | PDZ4 + PDZ5 | The Guk domain of PSD95/ SAP90 interacts with PDZ4+PDZ5 of MAGI2. Role in clustering NMDA receptor? | [40] |
FCHSD2 | F-BAR and double SH3 domains protein 2; Carom | Adapter protein. Promotes endocytosis of EGFR and down-regulation of EGFR signaling. Contributes to internalization of integrin β1 and transferrin receptor. Binds to membranes enriched in PtdIns(3,4)-P2 or PtdIns(3,4,5)P3. Promotes actin polymerization. | + | ND | ND | PDZ5 | MAGI1 colocalizes with Carom at immature cell contacts of epithelial cells. MAGI1 competes with CASK (calcium/calmodulin-dependent Ser protein kinase) for Carom binding. | [25] |
MAGI2; SSCAM; ACVRIP1; AIP1; ARIP1 | Membrane-associated guanylate kinase, WW, and PDZ domain-containing protein 2 | Scaffolding molecule containing 1 Guk domain, 2 WW domains, and 6 PDZ domains | ND | + | ND | PDZ4 + PDZ5 | MAGI2 dimerization might be involved in scaffolding, clustering, signaling | [30,40,44] |
MAGI3 | Membrane-associated guanylate kinase, WW, and PDZ domain-containing protein 3 | Scaffolding molecule containing 1 Guk domain, 2 WW domains, and 6 PDZ domains | ND | ND | + | ND | Frizzled-4 and Vangl2 form a ternary complex with MAGI3 via binding to PDZ1, suggesting MAGI3 oligomerization. Assumption supported by the interaction of wild-type MAGI3 with MAGI3pPA | [68] |
MAGI3pPA | MAGI3 with premature polyadenylation | A truncated form of MAGI3 (depletion PDZ2-5) resulting from the use of a cryptic intronic polyadenylation signal | ND | ND | + | ND | Prooncogenic; competition with full-length MAGI3 for controlling YAP1 signaling; increases nuclear YAP1 localization. Expressed especially in breast cancer | [42,90] |
CNKSR2; KSR2 | Connector enhancer of kinase suppressor of Ras 2 | Scaffolding protein with SAM, PDZ, and PH domains. Involved in MAPK pathways | ND | + | ND | PDZ4 and/or PDZ5 | Role in linking cell surface receptors to MAPK pathways? | [91] |
SHC | SHC-transforming protein | Couple activated receptor tyrosine kinases to the RAS pathway by recruitment of GRB2/SOS complex | + | ND | ND | PDZ4 and/or PDZ5 | MAGI1 interacts directly with NGF-R and SHC, positive regulation of NGF-stimulated SHC-ERK pathway | [28] |
TRIP6; ZRP1 | Thyroid receptor-interacting protein 6 | Member of the zyxin family contains 3 LIM domains. Localizes to focal adhesion and actin stress fibers. Regulates lysophosphatidic acid-induced cell migration. Modulates gene expression by nuclear translocation and interaction with some transcriptional factors, e.g., NFkB | + | ND | ND | PDZ5 | TRIP6 competes with β-catenin for binding MAGI1 PDZ5. Hence, TRIP6 impairs PTEN recruitment to E-cadherin/ β-catenin complexes and adherens junctions stabilization. In conjunction with AKT and NFkB activation by its core protein, TRIP6 promotes invasiveness. Displacement from MAGI1 allows β-catenin nuclear translocation and Wnt oncogenic signaling | [26,92] |
Intracellular Signaling Proteins | ||||||||
ARHGAP6 | Rho GTPase-activating protein 6 | GTPase activator for the Rho-type GTPases; Involved in the regulation of actin polymerization at the plasma membrane | + | ND | ND | PDZ2 | The antagonistic activities of NET1 and ARHGAP6 and their recruitment in the same molecular scaffold via two adjacent MAGI1 PDZ domains allow the fine-tuning of Rho signaling. The four last residues of NET1 and ARHGAP6 are identical, thus their selective binding to PDZ1 and PDZ2 of MAGI1 must be defined by residues upstream. | [67] |
ATN1 | Atrophin | Transcriptional corepressor. Associated with dentatorubral pallidoluysian atrophy, a rare neurodegenerative disorder | + | + | ND | WW | The first designation of MAGI2 was atrophin-1-interacting protein 1 (AIP1) as a novel partner of atrophin | [44] |
KRAS; Ki-Ras | GTPase KRas; K-Ras 2 | Proto-oncogene member of the small GTPase superfamily; upstream effector of PI3K and MAPK signaling pathways. | + | ND | ND | PDZ1 | Role in K-Ras 2 targeting to plasma membrane? Interaction not validated in mammalian cells | [29] |
LATS1/2 | Serine/threonine-protein kinase LATS1/2; Large tumor suppressor homolog 1/ 2 | Ser, Thr kinases. Negative regulators of YAP1 (Hippo signaling pathway). Involved in the control of cell cycle, a negative regulator of CDK1/cyclin A | + | + | + | WW | The PY motifs of LATS1/2 interact with the WW domain tandem of MAGIs. This tandem enables high affinity and specificity towards their ligands. | [34,93] |
MAP2K1, MEK1 | Dual specificity mitogen-activated protein kinase kinase 1; MEK1 MKK1 | Dual specificity protein kinase. Phosphorylates a Thr and a Tyr residue in a Thr-Glu-Tyr sequence of MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and transduction of the signal within the MAPK/ERK cascade | + | + | + | WW; GuK | MEK1 is necessary for PTEN membrane recruitment as part of a ternary complex involving MAGI1. Complex formation requires MEK1 phosphorylation by ERK and leads to the negative regulation of the AKT pathway | [94] |
NET1; ARHGEF8 | Neuroepithelial cell-transforming gene 1 protein | Rho guanine nucleotide exchange factor | + | ND | ND | PDZ1 | The antagonistic activities of NET1 and ARHGAP6 and their recruitment in the same scaffold via two adjacent MAGI1 PDZ domains allow the fine-tuning of Rho signaling. The four last residues of NET1 and ARHGAP6 are identical, thus their selective binding to PDZ1 and PDZ2 of MAGI1 must be defined by residues upstream. | [67,95] |
PLCB3 | 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3; PLC-beta-3 | Member of the phospholipase C-β family generates DAG and InsP3 from phosphatidylinositol in response to G-protein-linked receptor stimulation. | + | + | + | PDZ nd | MAGI3 competes with NHERF2 for binding to both LPAR2 and PLC-β3, decreases the activities of PLC-β3 and its downstream effector NFκB by facilitating LPAR2 coupling to different G proteins | [72,75] |
PTEN | Phosphatase and Tensin homolog deleted on chromosome TEN | Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase; Tumor suppressor | + | + | + | PDZ2 | PTEN stabilization, PTEN recruitment to high molecular weight molecular complexes, including E-cadherin junctional complexes. Stabilization of cell–cell junctions, decreased cell migration | [22,37,96,97,98] |
PTPN14; PTPD2; PEZ | Protein tyrosine phosphatase non-receptor type 14 | Tyr phosphatase with a FERM domain (cytoskeletal-associated proteins). Putative tumor suppressor. Dephosphorylates β-catenin at junctional complexes and stabilizes cell–cell contacts. Negatively regulates YAP1 (phosphatase dependent and independent manner) | +/− | + | + | WW | The PY motifs of PTPN14 interact with the WW domain tandem of MAGIs. This tandem enables high affinity and specificity towards their ligands. The inter-domain between the WW tandem might modulate the affinity of WW domains | [34] |
PTPN21; PTPD1 | Protein tyrosine phosphatase non-receptor Type 21 | Protein tyrosine phosphatase. Contains a FERM found in cytoskeletal-associated proteins. | ND | + | + | WW | The PY motifs of PTPN21 interact with the WW domain tandem of MAGIs. This tandem enables high affinity and specificity towards their ligands. | [34] |
RAPGEF2; NRap GEP; PDZ-GEF1 | Rap guanine nucleotide exchange factor 2; RA-GEF-1 | Guanine nucleotide exchange factor (GEF); activates the Rap and Ras family of small GTPases by exchanging bound GDP for free GTP in a cAMP-dependent manner | + | + | ND | PDZ0 (MAGI1; PDZ1 (MAGI2) | MAGI1 recruits RA-GEF-1 at tight junctions in epithelial cells. In endothelial cells, MAGI1 is required for Rap1 activation and adherens junction formation. Translocation of MAGI1 to cell–cell contacts is ascribed to its interaction with β-catenin. MAGI2 co-expressed with RA-GEF-1 enhances activation of Rap1 in podocytes, signaling essential for normal podocyte function | [99,100,101,102] |
SMAD3 | Mothers against decapentaplegic homolog 3; SMAD family member 3 | Effector of TGFβ and activin type 1 receptor kinases. Transmits signals from the cell surface to the nucleus. Forms heterodimer with SMAD4 and activates transcription. | ND | + | ND | WW | MAGI2 interacts with activin type 2 receptor via its PDZ5 and with SMAD3 via its WW domains. MAGI2 negatively regulates activin/ SMAD3 -induced gene transcription | [53] |
YAP1 | Yes-associated protein 1 | Regulator for TEAD transcription factors; coactivator and corepressor of gene expression downstream Hippo signaling pathway; Involved in cell growth, anchorage-independent growth, and EMT | ND | ND | + | PDZ5 | MAGI3 interacts with and sequesters YAP1 oncoprotein in the cytoplasm, inhibiting YAP1-induced malignant transformation of human mammary epithelial cells. | [42,90] |
Actin Associated Proteins | ||||||||
ACTN4 | Alpha-actinin-4 | Actin-binding protein | + | ND | ND | PDZ5 | Role in actin cytoskeleton dynamics? | [24] |
SYNPO | Synaptopodin | Actin-associated protein, involved in actin-based cell shape and motility | + | ND | ND | 2nd WW | Role in actin cytoskeleton dynamics? | [24] |
Posttranslational Modifications | ||||||||
CASP3 | Caspase-3; CASP-3 | Cysteine-aspartic acid protease. Effector caspase is involved in the execution phase of apoptosis. Activated by proteolytic cleavage. CASP-3 shares several substrates with CASP-7 but exerts distinct functions during apoptosis. | + | + | ND | Asp761 (MAGI1) | MAGI1 is cleaved by CASP-3 at Asp761, between PDZ2 and PDZ3. The N-term fragment translocates in the cytoplasm and the C-term accumulates in the nucleus. MAGI1 cleavages induce disruption of cell–cell contacts and apoptosis. MAGI2 cleavage site was not determined. | [103,104] |
CASP7 | Caspase7; CASP-7 | Cysteine-aspartic acid protease. Effector caspase is involved in the execution phase of apoptosis. Activated by proteolytic cleavage. CASP-7 shares several substrates with CASP-3 but exerts distinct functions during apoptosis. | + | ND | ND | Asp761 | MAGI1 is cleaved by CASP-7 at Asp761, generating 97 kDa and 68 kDa fragments. The N-term fragment translocates in the cytoplasm and the C-term accumulates in the nucleus. MAGI1 cleavages induce disruption of cell–cell contacts and apoptosis. | [103] |
RPS6KA1, P90RSK | Ribosomal protein S6 kinase alpha-1; S6K-alpha-1 | Ser/Thr kinase. Acts downstream ERK1/2. Mediates mitogenic and stress-induced activation via CREB1. Regulates translation through RPS6 and EIF4B. Mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. | + | ND | ND | Ser741 | Thrombin stimulates P90RSK that directly phosphorylates MAGI1 at Ser741 and induces MAGI1 deSUMOylation at Lys 931, leading to endothelial cells activation. This process involves Rap1 activation by phosphorylated MAGI1. SUMOylation impairs MAGI1 nuclear translocation and stabilizes endothelial barrier function. | [105,106] |
SENP2 | Sentrin/SUMO-Specific Protease SENP2 | Cysteine protease targeting members of small ubiquitin-like modifier (SUMO) protein family. Deconjugates sumoylated proteins | + | ND | ND | Lys 931 | MAGI1-K931 deSUMOylation induces both nuclear translocation of p90RSK-MAGI1 and ATF-6-MAGI1 complexes, which enhances endothelial cells activation and apoptosis, respectively. | [105] |
Viral (onco/) Proteins | ||||||||
Molecular Partners | Virus | Viral Protein Function | MAGI1 | Interaction MAGI2 | MAGI3 | MAGI Binding Domain | Biological Impact | References |
NS1 | Influenza A virus. RNA virus | Non-structural (NS) protein; non-essential virulence factor. Involved in inhibition of host immune responses (IFN production/ response) | + | + | + | PDZ nd | Sequesters MAGI1 from the plasma membrane. Does not seem to confer benefit to viral replication | [107,108] |
Tax | Human T-cell leukemia virus type 1 (HTLV-1). Retrovirus | Viral oncoprotein, immortalization of human T-cells. Promotes viral gene transcription and regulates expression of human genes by modulating CREB/ATF, NFkB, AP-1, and SRF pathways | + | MAGI2 mRNA not detectable in T-cell lines | + | PDZ1 | Downregulation of MAGI1 transcripts. Mis-localization of MAGI1, 3 to perinuclear region (from detergent-soluble to detergent-insoluble fraction). MAGI3 increases Tax1 accumulation | [109,110] |
E4-ORF1 | Human adenovirus type 9. DNA virus | Viral oncoprotein; PDZ binding motif required for E4-ORF1 -induced PI3K activation and cell transformation | + | ND | ND | PDZ1 and PDZ3 | Ad9 E4-ORF1 protein sequesters MAGI1 in the cytoplasm (from detergent-soluble to detergent-insoluble fraction). Altered tight junction assembly and cell polarity | [111,112,113,114] |
E6 | Human papillomavirus (HPV); high-risk HPV (HPV 16 and 18) causes cervical cancer. DNA virus | Viral oncoprotein interacts with and promotes degradation of TP53 as well as proteins with PDZ domains, including MAGIs | + | + | + | PDZ1 | HPV E6 proteins targets MAGI1 for proteasome degradation, leading to tight junction disruption. Restoration of MAGI1 expression in HPV positive cervix cancer HeLa cell line induces cell growth arrest and apoptosis. RNA aptamers to E6 inhibiting interaction with PDZ domain trigger cancer cell apoptosis | [111,115,116,117,118,119] |
E protein | Coronavirus (MERS-CoV). RNA virus | The envelope protein forms a transmembrane ion channel. PDZ binding motifs of E proteins from MERS and SARS-CoV/SARS-COV-2 differs and interact with distinct and shared cellular proteins with the PDZ domain | + | + | ND | PDZ5 | [120] |
Molecular Alterations | MAGI | Types of Cancer | Clinical Significance | References | ||
---|---|---|---|---|---|---|
Promoter Methylation | ||||||
MAGI1 | Anaplastic thyroid cancer | Malignant tumor associated with poor survival | [121] | |||
Lymphocytic leukemia | Decreased overall survival | [122] | ||||
MAGI2 | Breast cancer | Decreased overall survival | [128] | |||
Cervical cancer | [124] | |||||
Colon cancer | 32.8% exhibit MAGI2 hypermethylation | https://cancer.sanger.ac.uk/cosmic/ accessed on 22 July 2021 | ||||
Endometrium cancer | 34.9% exhibit MAGI2 hypermethylation | [126]; https://cancer.sanger.ac.uk/cosmic/ accessed on 22 July 2021 | ||||
Gastric cancer | Decreased progression-free survival | [125] | ||||
Ovarian cancer | Decreased overall survival | [126,127] | ||||
Rearrangement | ||||||
MAGI2 | Melanoma cell lines | [130] | ||||
Prostate cancer | [131] | |||||
MAGI3/AKT3 | Breast cancer | Enriched in triple-negative breast cancers | [132] | |||
miRNA Targeting | ||||||
miR-486-5p | MAGI1 | Erythroid leukemia K562 cell line | Decreased erythroid differentiation | [136] | ||
miR-520h | Renal cell carcinoma | Decreased overall survival | [137] | |||
miR-629-5p | MAGI2 | Ovarian cancer | miR-629-5p is downregulated in ovarian cancer | [138] | ||
miR-27a-3p | Breast cancer/ macrophages | Exosomal miR-27a-3p from breast cancer exhausts MAGI2 in macrophages, leading to downregulation of PTEN, increased PDL1 expression, and cancer cells’ immune escape. | [142] | |||
miR-487a | Breast cancer | miR-487a expression correlates with lymph node metastases | [139] | |||
miR-101 | Breast cell line (MCF7 cells) | [140] | ||||
miR-134/487b/655 cluster | Lung cancer cell lines | Epithelial–mesenchymal transition. Resistance to the EGFR inhibitor gefitinib, | [141] | |||
miR-4677-3p | Glioma | The GLIDR lncRNA sponges miR-4677-3p that exhausts MAGI2. MAGI2 overexpression promotes glioma cell lines proliferation. | [144] | |||
miR-34c-3p | MAGI3 | Hepatocarcinoma | Decreased overall survival | [143] | ||
Premature Polyadenylation | ||||||
MAGI3 | Breast cancer | Competition MAGI3pPa / wild-type MAGI3; activation YAP1 signaling | [42] | |||
MAGI1 Point Mutations | MAGI2 Point Mutations | MAGI3 Point Mutations | ||||
Tissue | % Mutated * | Tissue | % Mutated * | Tissue | % Mutated * | |
Liver | 16.5 | Prostate | 26.4 | Liver | 9.8 | |
Skin | 13.6 | Pancreas | 23.5 | Nervous system | 9.8 | |
Prostate | 13.4 | Liver | 21.2 | Skin | 8.2 | |
Pancreas | 12.3 | Breast | 17.8 | Prostate | 7.7 | |
Breast | 10.8 | Stomach | 14.4 | Biliary tract | 6.7 | |
Endometrium | 10.1 | Skin | 14.4 | Ovary | 6.2 | |
Nervous system | 9.8 | Esophagus | 14.3 | Breast | 6.1 | |
Ovary | 9.5 | Nervous system | 13.3 | Pancreas | 5.9 | |
Stomach | 9.2 | Ovary | 13.2 | Endometrium | 5,8 | |
Biliary tract | 8.9 | Endometrium | 10.2 | Esophagus | 5.6 |
MAGI | Types of Cancer | Transcript Accumulation * | Protein Expression * | Clinical Significance | References |
---|---|---|---|---|---|
MAGI1 | Breast cancer luminal | down | down | Decreased disease-free survival | [88] |
Breast cancer ER+/HER2− | down | down | High expression good prognosis | [147] | |
Colon cancer | down | nd | Decreased disease-free survival | [161] | |
Gastric cancer | down | down | Distant metastases | [146] | |
Gliomas | down | down | Distant metastases | [56] | |
Hepatocellular carcinoma | down | down | Poor prognosis | [145] | |
Kidney | High RNA level, increased overall survival | [162] http://gepia2.cancer-pku.cn, accessed on 26 July 2021 | |||
MAGI2 | Kidney | High RNA level, increased overall survival | [162] http://gepia2.cancer-pku.cn, accessed on 26 July 2021 | ||
Multiple myeloma | up | nd | Decreased overall survival | [156] | |
Ovarian cancer | down | nd | Decreased overall survival | [127] | |
Prostate | down | unaffected/down | High mRNA levels better prognosis | [149,150,151] | |
nd | up | [152,153,155] | |||
MAGI3 | Gliomas | down | down | Decreased overall survival | [55] |
Kidney | High RNA level, increased overall survival | [162] http://gepia2.cancer-pku.cn accessed on 26 July 2021 | |||
Ovarian cancer | down | nd | Decreased disease-free survival | [157] | |
Thyroid cancer | down | nd | Decreased RNA level in malignant vs benign tumors | [163] |
MAGI ceRNA | Primary Target | Secondary Target * | Activity, Function of Secondary Target | Physiological Impact | References | ||
---|---|---|---|---|---|---|---|
MAGI1-IT1 | |||||||
MAGI1-IT1 | miR-200a | ZEB1, ZEB2 (zinc finger E-Box binding homeobox 1/ 2) | Transcriptional repressor. Promotes epithelial to mesenchymal transition | Epithelial–mesenchymal transition, invasiveness. Ovarian cancer cell lines | [206] | ||
miR-302d-3p | IGF1 (insulin-like growth factor 1) | Structurally and functionally related to insulin. Growth-promoting activity through binding to IGF1R tyrosine kinase, leading to activation of the PI3K-AKT/PKB and the Ras-MAPK pathways. | Overexpression MAGI1-IT1 in gastric cancer is associated with poor overall survival. Knockdown in gastric cancer cell lines decreases proliferation in vitro and in vivo | [207] | |||
miR-512p-3p | AKT (protein kinase B, PKB) | Proto-oncogene. Ser/Thr kinase downstream of phosphatidylinositol 3-kinase (PI3K). Involved in cell proliferation, survival, and migration. | Increased AKT activity. Increased lung cancer cell lines proliferation | [205] | |||
MAGI2-AS3 Tumor Suppressor Activity | |||||||
MAGI2-AS3 | miR-15b-5p | CCDC19/CFAP45 (cilia and flagella associated protein 45) | Tumor suppressor. Inhibits cell proliferation | Inhibition of proliferation, migration, and invasion. Bladder cancer cell lines | [208] | ||
RECK * (reversion inducing cysteine-rich protein with kazal motifs; ST15, suppressor of tumorigenicity 15 protein) | Extracellular protein anchored to the plasma membrane. Decreases diffusible gelatinase/collagenase activity | Downregulation of miR15b-5p and miR-374a/b-5p by MAGI2-AS3 decrease the viability and migration of the epithelial ovarian cancer PEA1, KURAMOCHI, and SKOV3 cell lines. Downregulation of MAGI2-AS3 due to promoter hypermethylation | [209] | ||||
MTSS1 (metastasis suppressor protein 1) | Tumor suppressor controlling migration and invasion. Involved in Hedgehog and EGF pathways. Interacts with cytoskeleton | Downregulation of miR-15b-5p and miR-374a/b-5p by MAGI2-AS3 decrease the viability and migration of the epithelial ovarian cancer PEA1, KURAMOCHI, and SKOV3 cell lines. Downregulation of MAGI2-AS3 due to promoter hypermethylation | [209] | ||||
miR-23a-3p | PTEN * (phosphatase and tensin homolog deleted on chromosome 10) | Lipid and protein phosphatase. Dephosphorylates PtdIns(3,4,5)P3 produced by PI3K. Inhibits AKT pathway. Dephosphorylates proteins, e.g., FAK, IRS1, Dvl2, PTEN. Exerts activity independent of its phosphatase activity, e.g., DNA damage repair. Induces apoptosis, decreases cell proliferation and migration | Decreased proliferation, migration, and invasion. Increased apoptosis. Lung squamous carcinoma cell lines | [210,211] | |||
miR-25 | RECK * (reversion inducing cysteine-rich protein with kazal motifs; ST15, suppressor of tumorigenicity 15 protein) | Extracellular protein anchored to the plasma membrane. Decreases diffusible gelatinase/ collagenase activity | Decreased cell migration and invasiveness. Non-small cell lung carcinoma H1993 cell line | [212] | |||
miR-31-5p | TNS1 (tensin 1) | Focal adhesion molecule, crosslinks actin filaments. Involved in cell migration | Decreased proliferation, migration, and invasion of bladder cancer cell lines | [213] | |||
miR-155 | SOCS1 (suppressor of cytokine signaling 1) | Negative regulation of cytokines signaling through the JAK/STAT3 pathway | Decreased cell proliferation. Non-small cell lung carcinoma H1993 cell line | [214] | |||
miR-223-3p (according to the sequence in Ref. [215]) | EBP41L3 (erythrocyte membrane protein band 4.1 Like 3) | Tumor suppressor. Member of the band 4.1 family of cytoskeletal proteins. The linker between membrane proteins and cytoskeleton. Involved in cell adhesion and motility | Inhibition of the human cervix cancer SiHa and HeLa cell lines invasion and migration | [215] | |||
miR374a/b-5p | CADM2 (cell adhesion molecule 2) | Transmembrane protein involved in cell aggregation | Decreased proliferation and migration in vitro, enhanced apoptosis, decreased tumor growth, and experimental metastases in nude mice. Lung squamous carcinoma xxxSW900, SK-MES_1, and A549 and cell line. | [211] | |||
PTEN * (phosphatase and tensin homolog deleted on chromosome 10) | Lipid and protein phosphatase. Dephosphorylates PtdIns(3,4,5)P3 produced by PI3K. Inhibits AKT pathway. Dephosphorylates proteins, e.g., FAK, IRS1, Dvl2, PTEN. Exerts activity independent of its phosphatase activity, e.g., DNA damage repair. Induces apoptosis, decreases cell proliferation and migration | Downregulation of miR15b-5p and miR-374a/b-5p by MAGI2-AS3 decrease the viability and migration of the epithelial ovarian cancer PEA1, KURAMOCHI, and SKOV3 cell lines. Downregulation of MAGI2-AS3 due to promoter hypermethylation. Decreased migration and invasion of breast cancer cell lines | [209,216] | ||||
miR374b-5p | SMG1 (genitalia family member 1) | Ser/Thr protein kinase involved in nonsense-mediated decay of mRNAs containing premature Stop codons. Can phosphorylate and trigger TP53 activation after cell exposure to genotoxic stress | Decreased proliferation and migration. Hepatocarcinoma cell lines | [217] | |||
RECK * (reversion inducing cysteine-rich protein with kazal motifs; ST15, suppressor of tumorigenicity 15 protein) | Extracellular protein anchored to the plasma membrane. Decreases diffusible gelatinase/collagenase activity | Downregulation of miR15b-5p and miR-374a/b-5p by MAGI2-AS3 decrease the viability and migration of the epithelial ovarian cancer PEA1, KURAMOCHI, and SKOV3 cell lines. Downregulation of MAGI2-AS3 due to promoter hypermethylation | [209] | ||||
HOXA5 (homeobox A5) | Transcription factor upregulates the tumor suppressor p53 | Downregulation of miR15b-5p and miR-374a/b-5p by MAGI2-AS3 decrease the viability and migration of the epithelial ovarian cancer PEA1, KURAMOCHI, and SKOV3 cell lines. Downregulation of MAGI2-AS3 due to promoter hypermethylation | [209] | ||||
miR-525-5p | MDX1 (MAX dimerization protein) | Competes with MAX (Myc associated factor X) for interaction with the c-Myc proto-oncogene. Inhibits transactivation by this transcriptional activator complex | Decreases proliferation and migration of ovarian cancer cell lines | [218] | |||
EZH2 (Enhancer of zeste homolog 2; histone-lysine N-methyltransferase) | HOXB7 (homeobox B7) | Member of the homeobox family of transcription factors. Involved in cell proliferation and differentiation. Master regulatory gene orchestrating several oncogenic pathways. Overexpressed in various types of cancers including breast, esophageal, gastric, ovarian, and melanoma | MAGI2-AS3 binds to the HOXB7 promoter and recruits EZH2. Methylation of lysine 27 on histone H3 in the promoter region negatively regulates the transcription of HOXB7 and inhibits proliferation and radio-resistance of esophageal cancer cells. | [219] | |||
HEY1 (Hes related Family BHLH transcription factor with YRPW motif 1) | ACY1 (aminoacylase 1) | Involved in the hydrolysis of various N-acetylated amino acids. Putative tumor suppressor in clear cell renal cell carcinoma | MAGI2-AS3 forms a nucleoprotein complex with HEY1 in the nucleus and impairs its transcriptional repressor activity on the ACY1 promoter. Decreased cell viability, EMT, and migration in vitro; reduced tumor growth and angiogenesis in vivo. Clear cell renal cell carcinoma | [220] | |||
KDM1A (lysine demethylase 1A | RacGAP (Rac GTPase activating protein 1) | Negative regulation of Rho GTPase signaling through stimulation of GTP hydrolysis | Demethylation of Lys4 of histone H3 (H3K4Me2) at RACGAP1 promoter reduces transcription. Decreased proliferation and migration, enhanced apoptosis of HEPG2 hepatocarcinoma cells in vitro, and decreased tumor growth in nude mice | [221] | |||
TET1 (Tet Methylcytosine Dioxygenase 1) | MAGI2 (membrane-associated guanylate kinase inverted 2) | Scaffolding molecule with 1 Guanylate Kinase domain, 2 WW domains, and 6 PDZ Domains. Involved in junctional complexes stability and cell signaling | Demethylation of MAGI2 promoter, increased MAGI2 expression, inhibition of AKT and Wnt/ β-catenin pathways; decreased cell proliferation of MCF-7 breast cancer cell line | [128] | |||
TET2 (Tet Methylcytosine Dioxygenase 2) | LRIG1 (leucine-rich repeats and immunoglobulin-like domains 1) | Transmembrane protein that interacts and negatively regulates receptor tyrosine kinases of the EGFR family, MET and RET by enhancing receptor ubiquitination and degradation | Impaired leukemia stem cells self-renewal | [222] | |||
? | ? | FAS (Fas cell surface death receptor); FASL (FAS ligand) | Members of the TNF/ TNF receptor family. Promotes activation of caspase-8 and triggers the apoptotic cascade | Decreased proliferation, enhanced apoptosis of MDA-MB-231 and MCF-7 breast cancer cell lines. The underlying mechanism has not been characterized but might involve miR-374a -a target of MAGI2-AS3- that exhausts FAS transcripts | [223] | ||
? | ? | ROCK2 (Rho-associated coiled-coil containing protein kinase 2) | Ser/Thr kinase, a downstream effector of the Rho GTPase. Involved in the regulation of actin cytoskeleton organization, stress fiber and focal adhesion formation, cell adhesion, and motility | MAGI2-AS3 induces the downregulation of ROCK2 at both RNA and protein levels in the Hep3B and MHCC97-H hepatocarcinoma cell lines decrease cell migration and invasiveness and induce apoptosis. | [224] | ||
MAGI2-AS3 Tumor Promoter Activity | |||||||
MAGI2-AS3 | miR-141 | ZEB1 * (zinc finger E-box binding homeobox 1) | Transcriptional repressor. Promotes epithelial to mesenchymal transition | Increased migration and invasion of gastric cancer cell lines | [225] | ||
miR-143 | AKT, COX2, ERK5, HMBG1, IGF1-R, PAI-1 ? | MiR-143 functions as a tumor suppressor in human bladder cancers. Known targets of miR-143 in bladder cancers cells are AKT, Cox2, ERK5, HMBG1, IGF1-R, PAI-1 | [226] | ||||
miR-200a | ZEB1 *, ZEB2 (zinc finger E-box binding homeobox 1/ 2) | Transcriptional repressor. Promotes epithelial to mesenchymal transition | Increased migration and invasion of gastric cancer cell lines. The bromodomain-containing 4 (BRD4) protein, an acetylated histone binding protein is a transcriptional activator of MAGI2-AS3 in gastric cancer. MiR-200a increases E-cadherin levels, inhibits migration, and enhances the sensitivity of bladder cancer cell lines to anti-EGFR therapies. | [225,226,227] | |||
miR-218-5p | GDPD5 (glycerophosphodiester phosphodiesterase domain containing 5) | Involved in glycerol metabolism. Mediates the cleavage of glycosylphosphatidylinositol -anchor of RECK, leading to RECK release from the plasma membrane | Increased proliferation, migration, epithelial–mesenchymal transition, and cisplatin resistance of nasopharyngeal epithelial cell lines | [228] | |||
miR-3163 | TMEM106B (transmembrane protein 106B) | Involved in the regulation of lysosomal trafficking | Decreased apoptosis, increased proliferation, and migration of the HCT116 and RKO colon cancer cell lines | [229] |
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Kotelevets, L.; Chastre, E. A New Story of the Three Magi: Scaffolding Proteins and lncRNA Suppressors of Cancer. Cancers 2021, 13, 4264. https://doi.org/10.3390/cancers13174264
Kotelevets L, Chastre E. A New Story of the Three Magi: Scaffolding Proteins and lncRNA Suppressors of Cancer. Cancers. 2021; 13(17):4264. https://doi.org/10.3390/cancers13174264
Chicago/Turabian StyleKotelevets, Larissa, and Eric Chastre. 2021. "A New Story of the Three Magi: Scaffolding Proteins and lncRNA Suppressors of Cancer" Cancers 13, no. 17: 4264. https://doi.org/10.3390/cancers13174264
APA StyleKotelevets, L., & Chastre, E. (2021). A New Story of the Three Magi: Scaffolding Proteins and lncRNA Suppressors of Cancer. Cancers, 13(17), 4264. https://doi.org/10.3390/cancers13174264