MAGI3

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: PAINT infers cytoplasmic activity for MAGI3 from conserved MAGUK-family scaffold biology. MAGI3 is a soluble peripheral-membrane protein, and its signaling and ubiquitin-adaptor activities occur on the cytoplasmic side of membranes or within intracellular compartments. Reason: Cytoplasm is plausible and not contradicted, but it is too broad to identify MAGI3's defining sites of action. Direct studies more specifically place MAGI3 at tight/cell-cell junctions, selected plasma-membrane sites, and in the nucleus; those locations should carry the core interpretation.
GO:0005911 cell-cell junction	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference places MAGI3 at cell-cell junctions, consistent with direct localization at epithelial tight junctions and E-cadherin-based contacts. Reason: Cell-cell junctions are a defining site of MAGI3 scaffold activity. Direct human-cell imaging independently corroborates the conserved IBA assignment. Supporting Evidence: PMID:12615970 In epithelial cells, MAGI-3 was localized with ZO-1 and cingulin at tight junctions, whereas in primary cultured astrocytes it was found in E-cadherin-based cell-cell contacts and in focal adhesion sites.
GO:0007165 signal transduction	IBA GO_REF:0000033	MODIFY	Summary: PAINT correctly identifies a conserved relationship to signaling, but MAGI3 is a scaffold that modulates assembled signaling pathways rather than a generic signal-transducing enzyme. Reason: Regulation of signal transduction describes the evidence more precisely. MAGI3 can attenuate adrenergic-receptor ERK output, support LPA2-dependent ERK/RhoA output, and regulate PTEN-AKT signaling according to the recruited complex. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000817101 SUPPORTS TRANSFER The PAINT source node correctly supports conserved signaling involvement across MAGUK scaffolds, but the undifferentiated process term does not capture MAGI3's experimentally established regulatory role. Proposed replacements: regulation of signal transduction Supporting Evidence: PMID:16904289 These results demonstrate that MAGI-3 interacts directly with LPA(2) and regulates the ability of LPA(2) to activate Erk and RhoA.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: The UniProt location mapping assigns MAGI3 to the nucleus; direct immunofluorescence and immunoelectron microscopy also detected nuclear MAGI3. Reason: This electronic annotation is independently supported by direct human-cell localization and is relevant to MAGI3 interactions with nuclear signaling proteins such as YAP and c-Myc. Supporting Evidence: PMID:12615970 Immunofluorescence and immunoelectron microscopy revealed that MAGI-3 is concentrated in specific sites at the plasma membrane and in the nucleus. file:human/MAGI3/MAGI3-deep-research-manual.md Immunofluorescence and immunoelectron microscopy placed MAGI3 at selected plasma-membrane sites, in nuclei, at epithelial tight junctions, at E-cadherin contacts, and at focal adhesions.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular-location mapping places peripheral MAGI3 at the plasma membrane, matching direct imaging and its receptor/phosphatase scaffold functions. Reason: Direct localization and biochemical studies support selected plasma-membrane sites as a major location where MAGI3 brings receptors, phosphatases, and substrates together. Supporting Evidence: PMID:12615970 Immunofluorescence and immunoelectron microscopy revealed that MAGI-3 is concentrated in specific sites at the plasma membrane and in the nucleus.
GO:0005923 bicellular tight junction	IEA GO_REF:0000044	ACCEPT	Summary: UniProt mapping assigns MAGI3 to bicellular tight junctions, consistent with two direct localization studies in epithelial cells. Reason: Tight junction is the best-established, functionally relevant MAGI3 localization. The electronic annotation is corroborated by direct imaging and should be retained. Supporting Evidence: PMID:10748157 localizes to epithelial cell tight junctions
GO:0046037 GMP metabolic process	IEA GO_REF:0000108	REMOVE	Summary: This logical inference is downstream of the NAS GMP-kinase assignment. It reflects the historical MAGUK-family name rather than MAGI3 biochemistry. Reason: MAGI3's guanylate-kinase-like region is explicitly described as catalytically inactive, and no inspected study demonstrates GMP conversion or a role in GMP metabolism. The source molecular-function premise is false for this scaffold. Supporting Evidence: PMID:27205883 MAGI3 is a scaffolding protein with 2 WW and 6 PDZ domains, along with a catalytically inactive region of homology to the yeast guanylate kinase
GO:0046710 GDP metabolic process	IEA GO_REF:0000108	REMOVE	Summary: GDP metabolism was inferred automatically from the erroneous GMP-kinase annotation and is not supported by direct MAGI3 biochemistry. Reason: The guanylate-kinase-like region is a noncatalytic scaffold module. Without GMP kinase activity, the associated GDP metabolic-process inference has no valid mechanistic basis. Supporting Evidence: PMID:27205883 catalytically inactive region of homology to the yeast guanylate kinase
GO:0005515 protein binding	IPI PMID:15652357 Identification of MAGI-3 as a transforming growth factor-alp...	MARK AS OVER ANNOTATED	Summary: The study demonstrates PDZ1-dependent binding of MAGI3 to pro-TGF-alpha and links that interaction to epithelial cell-surface trafficking. Reason: The underlying interaction is informative, but generic protein binding does not describe MAGI3's scaffold/adaptor activity or the trafficking outcome. Partner-specific interaction evidence should be retained outside a vague molecular-function annotation. Supporting Evidence: PMID:15652357 In vitro, proTGFalpha bound the PDZ-1 domain of MAGI-3 and MAGI-2, but not MAGI-1.
GO:0005515 protein binding	IPI PMID:16316992 Proteomic analysis of beta1-adrenergic receptor interactions...	MARK AS OVER ANNOTATED	Summary: The paper maps beta1-adrenergic-receptor tail binding to MAGI3 PDZ1 and shows selective regulation of receptor-induced ERK1/2 activation. Reason: Generic protein binding discards the domain specificity and functional signaling consequence. The interaction supports molecular-adaptor and ERK regulation annotations rather than GO:0005515 as a core activity. Supporting Evidence: PMID:16316992 The beta1AR carboxyl terminus was found to bind specifically to the first PDZ domain of MAGI-3
GO:0005515 protein binding	IPI PMID:16964398 EG-1 interacts with c-Src and activates its signaling pathwa...	MARK AS OVER ANNOTATED	Summary: GOA records a MAGI3-MED28/EG-1 interaction. The cached abstract reports EG-1 association with multiple WW-domain proteins but does not name MAGI3, and the full text was unavailable for independent pair-level assessment. Reason: This action does not reject the experimental interaction. It records that generic protein binding remains uninformative even if the pair is valid; pair-level confidence should be revisited from the full paper or source interaction record. Supporting Evidence: PMID:16964398 EG-1 shows interaction with multiple other SH3- and WW-containing molecules involved in various signaling pathways.
GO:0005515 protein binding	IPI PMID:20353789 Beta-2 adrenergic receptor mediated ERK activation is regula...	MARK AS OVER ANNOTATED	Summary: The study demonstrates MAGI3 PDZ5 binding to the beta2-adrenergic-receptor tail and a resulting delay in receptor-stimulated ERK1/2 activation. Reason: The specific receptor-scaffold mechanism is sound, but GO:0005515 does not convey it. The evidence is better represented by molecular-adaptor and ERK regulation annotations. Supporting Evidence: PMID:20353789 The carboxyl terminus of beta2AR binds with high affinity to the fifth PDZ domain of MAGI-3
GO:0005515 protein binding	IPI PMID:21799911 Ubiquitin ligase RNF146 regulates tankyrase and Axin to prom...	MARK AS OVER ANNOTATED	Summary: GOA records an RNF146 interaction from a Wnt-pathway ubiquitin-ligase study. MAGI3 is not named in the locally extracted main text, so the pair may derive from supplemental interaction data. Reason: The review does not dispute a supplemental pair that cannot be independently inspected here. Regardless, generic protein binding is not a useful molecular function for MAGI3 and should not be treated as core.
GO:0005515 protein binding	IPI PMID:23873930 Cellular localization and characterization of cytosolic bind...	MARK AS OVER ANNOTATED	Summary: Full-text WW-domain arrays and GST pulldown experiments demonstrate binding between PRRG4 and MAGI3 and map contributions from PRRG4 proline-rich motifs. Reason: This is direct interaction evidence, but GO:0005515 loses the WW-domain specificity and provides no defined biological outcome. It is useful partner context rather than a core molecular-function term. Supporting Evidence: PMID:23873930 All the tested WW domain-containing proteins (YAP1, YAP2, WWTR1, MAGI-1, MAGI-3, NEDD4, NEDD4L) bound to GST-PRRG4cyto but not to the GST-only control
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: BioPlex contributes MAGI3 interaction candidates (GOA aggregates CIT and DLGAP4 in this term-reference group) from cell-line-specific affinity-purification networks. Reason: Proteome-scale interaction candidates can guide mechanistic follow-up, but a network edge does not define a specific MAGI3 activity. Generic protein binding should not be elevated to core function. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks.
GO:0005515 protein binding	IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac...	MARK AS OVER ANNOTATED	Summary: Quantitative fragmentomics contributes a large set of PDZ-domain/PDZ-binding motif interactions for MAGI3, including host and viral partners aggregated in this GOA group. Reason: The interaction-affinity matrix is valuable partner-level information, but generic protein binding obscures PDZ specificity and says nothing about which interactions function in vivo. It is not a core molecular activity term. Supporting Evidence: PMID:36115835 Here, we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM)
GO:0070160 tight junction	IDA PMID:10748157 Interaction of the tumor suppressor PTEN/MMAC with a PDZ dom...	ACCEPT	Summary: The founding human MAGI3 study directly localized the protein to epithelial tight junctions while characterizing its PTEN scaffold activity. Reason: This is direct evidence for MAGI3's defining junctional site of activity and is consistent with independent imaging and the more specific bicellular tight-junction annotation. Supporting Evidence: PMID:10748157 localizes to epithelial cell tight junctions
GO:0140767 enzyme-substrate adaptor activity	IDA PMID:10748157 Interaction of the tumor suppressor PTEN/MMAC with a PDZ dom...	ACCEPT	Summary: MAGI3 binds the PTEN phosphatase and positions it near phospholipid signaling substrates; an independent study shows MAGI3 linking receptor tyrosine phosphatase beta to a protein substrate. Reason: Bringing an enzyme together with its substrate is the experimentally established core activity of this multidomain scaffold and matches the current GO definition precisely. MAGI3 itself is not assigned the enzymes' catalytic activities. Supporting Evidence: PMID:10748157 MAGI3 allows for the juxtaposition of PTEN/MMAC to phospholipid signaling pathways involved with cell survival. PMID:12615970 These findings suggest a possible role for MAGI-3 as a scaffolding molecule that links receptor tyrosine phosphatase with its substrates at the plasma membrane.
GO:0030054 cell junction	IDA GO_REF:0000052	ACCEPT	Summary: Human Protein Atlas immunofluorescence places MAGI3 at cell junctions, in agreement with direct tight-junction and E-cadherin-contact studies. Reason: Although broad, cell junction is correct and experimentally supported. The review also retains more informative cell-cell and tight-junction terms. Supporting Evidence: PMID:12615970 In epithelial cells, MAGI-3 was localized with ZO-1 and cingulin at tight junctions
GO:0004385 GMP kinase activity	NAS PMID:10748157 Interaction of the tumor suppressor PTEN/MMAC with a PDZ dom...	REMOVE	Summary: This historical annotation appears to interpret the MAGUK-family guanylate-kinase-like domain as a catalytic guanylate kinase; the cited paper reports scaffold interactions and no GMP kinase assay. Reason: Direct MAGI3 literature explicitly describes the homologous region as catalytically inactive. The protein name and fold are insufficient to assign GMP kinase activity, and the annotation drives two incorrect metabolic IEAs. Supporting Evidence: PMID:27205883 MAGI3 is a scaffolding protein with 2 WW and 6 PDZ domains, along with a catalytically inactive region of homology to the yeast guanylate kinase
GO:0006915 apoptotic process	NAS PMID:10748157 Interaction of the tumor suppressor PTEN/MMAC with a PDZ dom...	MODIFY	Summary: The paper discusses apoptosis as a downstream consequence of PTEN-AKT signaling and shows that MAGI3 and PTEN cooperate to modulate AKT, but does not establish MAGI3 as an execution component of apoptosis. Reason: The supported proximal process is regulation of PI3K/AKT signal transduction. Replacing the broad downstream phenotype avoids implying direct participation in the apoptotic machinery. Proposed replacements: regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction Supporting Evidence: PMID:10748157 Importantly, MAGI3 and PTEN/MMAC cooperate to modulate the kinase activity of AKT/PKB.
GO:0016020 membrane	NAS PMID:10748157 Interaction of the tumor suppressor PTEN/MMAC with a PDZ dom...	MODIFY	Summary: MAGI3 is a peripheral membrane scaffold concentrated at epithelial tight junctions and selected plasma-membrane sites; it is not an integral membrane protein. Reason: The generic membrane term is directionally correct but discards the direct, specific localization. Plasma membrane and bicellular tight junction are better replacements and avoid ambiguity about internal membranes. Proposed replacements: plasma membrane bicellular tight junction Supporting Evidence: PMID:12615970 MAGI-3 is concentrated in specific sites at the plasma membrane and in the nucleus.
GO:0035556 intracellular signal transduction	NAS PMID:10748157 Interaction of the tumor suppressor PTEN/MMAC with a PDZ dom...	MODIFY	Summary: MAGI3 participates in intracellular signaling by organizing PTEN with membrane-proximal phospholipid pathways and modulating AKT activity. Reason: The generic term is valid in essence but too broad. The cited paper directly supports the more informative regulation of PI3K/AKT signal transduction. Proposed replacements: regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction Supporting Evidence: PMID:10748157 MAGI3 and PTEN/MMAC cooperate to modulate the kinase activity of AKT/PKB.
GO:1990756 ubiquitin-like ligase-substrate adaptor activity	IDA PMID:35864508 E3 ubiquitin ligase MAGI3 degrades c-Myc and acts as a predi...	NEW	Summary: Proposed new annotation. MAGI3 binds c-Myc through PDZ5 and SKP1 through PDZ2, thereby recruiting c-Myc to a SKP1-CUL1 ubiquitin-ligase assembly. Reason: The experiments directly establish substrate recognition and bridging, which match ubiquitin-like ligase-substrate adaptor activity. This is more accurate than assigning catalytic ubiquitin-protein transferase activity to MAGI3. Supporting Evidence: PMID:35864508 these results demonstrate the existence of a macromolecular complex c-Myc-MAGI3-SKP1-CUL1 PMID:35864508 MAGI3 subsequently binds c-Myc through PBM of c-Myc at its carboxyl terminal and the fifth PDZ domain of MAGI3 to associate c-Myc with the SKP1-Cullin E3 ligase
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IMP PMID:35864508 E3 ubiquitin ligase MAGI3 degrades c-Myc and acts as a predi...	NEW	Summary: Proposed new annotation. MAGI3 gain and loss alter c-Myc K48 polyubiquitylation, protein half-life, and proteasome-dependent degradation in colorectal-cancer cells. Reason: Perturbation, proteasome-inhibitor, and ubiquitylation assays establish a causal role for MAGI3 in targeting c-Myc to ubiquitin-dependent proteasomal degradation. Supporting Evidence: PMID:35864508 MAGI3 modulates c-Myc protein stability by promoting c-Myc ubiquitin–proteasome degradation
GO:0031461 cullin-RING ubiquitin ligase complex	IDA PMID:35864508 E3 ubiquitin ligase MAGI3 degrades c-Myc and acts as a predi...	NEW	Summary: Proposed new annotation. Co-immunoprecipitation detected MAGI3 with c-Myc, SKP1, and CUL1, and domain-resolved pulldown mapped direct SKP1 binding to MAGI3 PDZ2. Reason: These data place MAGI3 as the substrate-recognition component of a CUL1-based ubiquitin-ligase assembly. The broader cullin-RING complex term is used because MAGI3 substitutes for a conventional F-box substrate receptor. Supporting Evidence: PMID:35864508 MAGI3 interacted with c-Myc, SKP1 and CUL1 in RKO cell.
GO:0070372 regulation of ERK1 and ERK2 cascade	IDA PMID:16316992 Proteomic analysis of beta1-adrenergic receptor interactions...	NEW	Summary: Proposed new annotation. MAGI3 attenuates beta1- and beta2-adrenergic receptor-driven ERK1/2 activation, while endogenous MAGI3 supports LPA2-driven ERK activation in SW480 cells. Reason: Multiple direct perturbation studies establish ERK1/2 regulation. The neutral regulation term accurately accommodates receptor- and cell-context-dependent effects in opposite directions. Supporting Evidence: PMID:16316992 MAGI-3 co-expression with beta1AR profoundly impaired beta1AR-mediated ERK1/2 activation PMID:16904289 silencing of MAGI-3 expression by siRNA drastically inhibited LPA-induced Erk activation
GO:0043507 positive regulation of JUN kinase activity	ISS PMID:15195140 MAGI-3 is involved in the regulation of the JNK signaling pa...	NEW	Summary: Proposed new annotation by orthology. Mouse MAGI3 forms a FZD4-Ltap/Vangl2 scaffold at cell contacts and strongly activates JNK with those partners in a Rac-dependent manner. Reason: The domain architecture and pathway partners are conserved, supporting a cautious human ISS annotation. The evidence is direct for mouse MAGI3, so the transfer is explicitly distinguished from direct human evidence. Supporting Evidence: PMID:15195140 MAGI-3 strongly activated JNK in conjunction with frizzled-4 and Ltap, and that this activation required the small GTPase, Rac.

Gene Description

Existing Annotations Review

Core Functions

MAGI3 uses its PDZ and WW domains to assemble junctional receptor, phosphatase, and substrate complexes, positioning enzymes such as PTEN and PTPRB near their membrane-proximal substrates and thereby regulating PI3K-AKT, ERK, and related intracellular signaling pathways.

MAGI3 acts as a substrate-recognition adaptor in a CUL1-SKP1 ubiquitin-ligase assembly, binding c-Myc and promoting its K48-linked ubiquitylation and proteasome-dependent degradation.

References

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