MAGI3

MAGI3 is a multi-PDZ/WW domain scaffold protein at epithelial tight junctions and cell–cell contacts that restrains multiple oncogenic signaling pathways by physically organizing receptors, phosphatases, and signaling effectors at the membrane (PMID:10748157, PMID:12615970). Through its PDZ domains it directly binds the tumor suppressor PTEN to modulate AKT/PKB activity, and MAGI3 levels positively control PTEN protein and suppress PI3K/Akt signaling and proliferation (PMID:10748157, PMID:26248734). A central tumor-suppressive function is the negative regulation of β-catenin: MAGI3 binds the C-terminal PDZ-binding motif of β-catenin, disrupting its intramolecular N-terminus–ARM interaction to expose phosphorylation sites, enabling GSK-3β-mediated phosphorylation and ubiquitin-dependent degradation, thereby suppressing β-catenin transcriptional output (Cyclin D1, Axin2, c-Myc) and downstream programs including the Warburg effect (PMID:26452219, PMID:32080912, PMID:41876458). MAGI3 also acts as the substrate-recognition subunit of a SKP1-Cullin E3 ubiquitin ligase that ubiquitinates c-Myc for proteasomal degradation (PMID:35864508). As a PDZ scaffold it engages numerous transmembrane partners—RPTPβ and its tyrosine-phosphorylated substrates (PMID:12615970), frizzled-4/-7 and Ltap to activate JNK through Rac (PMID:15195140), LPA2 and β2-adrenergic receptors where it competes with pro-oncogenic PDZ proteins such as NHERF-2 to bias G-protein coupling and dampen ERK/RhoA/PLC signaling (PMID:16904289, PMID:20353789, PMID:21134377), and pro-TGFα for basolateral trafficking (PMID:15652357). MAGI3's growth-restraining activity is antagonized by viral oncoproteins (HPV E6 drives its proteasomal degradation by a ubiquitin-independent route; HTLV-1 Tax1 mislocalizes it) and by premature cleavage/polyadenylation that yields a dominant-negative truncated isoform releasing YAP from inhibition (PMID:12140759, PMID:18518978, PMID:15003862, PMID:27205883, PMID:34510826).

1. 2000 High

   Established MAGI3 as a tight-junction scaffold that physically tethers the tumor suppressor PTEN to modulate AKT signaling, defining its first growth-regulatory function.

   Evidence Co-IP, pulldown, tight-junction localization, and AKT kinase assay in epithelial cells

   PMID:10748157

   Open questions at the time

   • Did not establish stoichiometry or whether PTEN catalytic regulation is direct
   • No in vivo phenotype for the MAGI3–PTEN axis
2. 2002 High

   Showed MAGI3 is a target of high-risk HPV E6 oncoproteins, framing its degradation as part of viral transformation and implying a tumor-suppressive role.

   Evidence Co-expression degradation assays with dominant-negative PDZ competition and proteasome inhibition

   PMID:12140759

   Open questions at the time

   • Mechanism of degradation not resolved here
   • Endogenous consequence of MAGI3 loss not measured
3. 2003 High

   Defined MAGI3 as a PDZ scaffold for receptor tyrosine phosphatase RPTPβ required for efficient substrate dephosphorylation, broadening its role to organizing phosphatase–substrate complexes.

   Evidence Y2H, Co-IP, pulldown, immuno-EM localization, and phosphatase substrate assay in glioblastoma and Caco2 cells

   PMID:12615970

   Open questions at the time

   • Identity of the 130/90 kDa substrates not determined
   • Functional consequence of altered substrate phosphorylation unclear
4. 2004 Medium

   Demonstrated MAGI3 nucleates a frizzled-4/-7–Ltap ternary complex that activates JNK via Rac, and that HTLV-1 Tax1 binds and relocalizes MAGI3, linking the scaffold to planar/non-canonical Wnt signaling and viral transformation.

   Evidence Co-IP, colocalization, JNK activation with dominant-negative Rac; differential display and transformation assay for Tax1

   PMID:15003862 PMID:15195140

   Open questions at the time

   • Tax1–transformation link is correlative
   • Physiological context for frizzled-driven JNK activation not defined
5. 2006 High

   Identified MAGI3 as a selective LPA2-receptor partner required for LPA-induced ERK and RhoA signaling, showing the scaffold can both promote and restrain receptor outputs depending on context.

   Evidence PDZ proteomic array, co-affinity purification, LPA2 C-terminal mutagenesis, siRNA, ERK/RhoA assays

   PMID:16904289

   Open questions at the time

   • Did not reconcile positive ERK/RhoA role with later negative regulatory findings
   • Downstream cellular phenotype not assessed
6. 2008 Medium

   Resolved the mechanism of HPV E6-mediated MAGI3 loss as ubiquitin-independent and proteasome-resistant, mechanistically distinguishing it from E6/MDM2-driven p53 degradation.

   Evidence Proteasome inhibitor and in vivo ubiquitination assays comparing MAGI3 and p53

   PMID:18518978

   Open questions at the time

   • The actual proteolytic route remains undefined
   • Single lab
7. 2010 High

   Established MAGI3 as a negative regulator of GPCR signaling that biases G-protein coupling by competing with NHERF-2 at LPA2 and binds β2AR, dampening ERK, PLC, NF-κB, migration and invasion.

   Evidence Co-IP, PDZ binding assays, inositol phosphate/NF-κB reporter, migration/invasion assays with OE and KD

   PMID:20353789 PMID:21134377

   Open questions at the time

   • How MAGI3 selects Gα12 vs Gαq coupling structurally is unknown
   • Relationship to its earlier positive ERK role at LPA2 unresolved
8. 2015 High

   Defined MAGI3 as a direct β-catenin binder that suppresses Wnt transcriptional output and tumor growth, and confirmed its PTEN/Akt-suppressive role in glioma, consolidating its tumor-suppressor identity.

   Evidence GST pulldown, Co-IP, β-catenin luciferase reporter, OE/KD, and xenograft assays in glioma

   PMID:26248734 PMID:26452219

   Open questions at the time

   • Did not specify how MAGI3 binding promotes β-catenin degradation
   • Endogenous-level requirement in normal tissue untested
9. 2016 High

   Revealed a regulatory mechanism by which premature cleavage/polyadenylation generates a dominant-negative MAGI3 isoform that blocks the full-length protein from inhibiting YAP, promoting transformation.

   Evidence RNA isoform identification, dominant-negative OE, MAGI3–YAP Co-IP, and transformation assay in mammary epithelial cells

   PMID:27205883

   Open questions at the time

   • The MAGI3–YAP binding interface not mapped
   • Prevalence of the truncated isoform in primary tumors not quantified
10. 2022 High

    Showed MAGI3 itself functions as a substrate-recognition subunit of a SKP1-Cullin E3 ligase that ubiquitinates c-Myc for degradation, adding an enzymatic adaptor role beyond passive scaffolding.

    Evidence Co-IP, GST pulldown, ubiquitination assay, proliferation/apoptosis and xenograft assays in colorectal cancer

    PMID:35864508

    Open questions at the time

    • The specific Cullin/F-box partners were not fully defined
    • How this E3 role integrates with β-catenin-mediated c-Myc control is unclear
11. 2026 Medium

    Provided a structural mechanism for β-catenin regulation: MAGI3 binding disrupts β-catenin's intramolecular N-terminus–ARM interaction to expose GSK-3β phosphorylation sites and license its degradation, with loss driving mTOR-inhibitor resistance.

    Evidence Multi-omics, Co-IP, PDZ binding, phosphorylation/ubiquitination assays, metastasis and drug-resistance assays in ccRCC

    PMID:41876458

    Open questions at the time

    • Conformational model not yet independently replicated
    • No direct structural data for the proposed β-catenin conformational change

• How MAGI3's distinct activities—PDZ scaffolding, E3 ligase adaptor function, and conformational regulation of β-catenin—are coordinated and selected in different tissues remains unresolved.
• No structural model of full-length MAGI3 multivalent assembly
• Tissue-specific partner selection rules undefined
• No germline loss-of-function disease association established in the corpus