MPP2

MPP2 is a MAGUK p55 subfamily scaffold protein that organizes signaling complexes at postsynaptic sites and epithelial cell junctions through its PDZ, SH3, and GK domains. At glutamatergic synapses, MPP2 localizes to the periphery of the postsynaptic density, where its PDZ domain binds the synaptic adhesion molecule SynCAM1 and its SH3-GK module engages core PSD scaffolds PSD-95 and GKAP; it additionally recruits GABA-A receptor subunits to dendritic spines, modulating inhibitory synaptic transmission, and interacts with SK2 potassium channels in the basolateral amygdala to regulate neuronal excitability during fear extinction (PMID:27756895, PMID:35312684, PMID:37469037). In cerebellar granule cells, MPP2 forms a complex with CADM1, CASK, and Lin7 and is required for proper Lin7 distribution at synaptic membranes (PMID:35854144). A de novo MPP2 p.K315N missense mutation confers susceptibility to Vogt-Koyanagi-Harada autoimmune uveitis by enhancing binding to ANXA2 and activating the ERK3/IL-17E inflammatory pathway, establishing a direct disease link (PMID:37828081).

1. 2009 Medium

   The first functional characterization of MPP2 outside neurons revealed that its PDZ domain engages the tyrosine kinase c-Src and that MPP2 negatively regulates c-Src activity, establishing a role in maintaining epithelial actin cytoskeletal organization.

   Evidence PDZ domain array screen, co-immunoprecipitation, kinase activity assay, and actin morphology readout in MCF-10A breast epithelial cells

   PMID:19665017

   Open questions at the time

   • No in vivo validation of the MPP2–c-Src interaction
   • Mechanism by which MPP2 inhibits c-Src kinase activity is undefined
   • Relevance of this epithelial role to neuronal MPP2 function not addressed
2. 2016 Medium

   MPP2 was shown to be a postsynaptic scaffold that bridges SynCAM1 (via its PDZ domain) to core PSD components PSD-95 and GKAP (via its SH3-GK module), establishing its domain-specific wiring logic at excitatory synapses.

   Evidence Co-immunoprecipitation, direct PDZ–SynCAM1 C-terminus binding assay, and immunofluorescence in rat hippocampal neurons

   PMID:27756895

   Open questions at the time

   • Functional consequence of disrupting the MPP2–SynCAM1 link on synaptic transmission was not tested
   • Structural basis of the SH3-GK interaction with PSD-95/GKAP not resolved
   • Single-lab study without independent replication
3. 2022 High

   Superresolution imaging and quantitative proteomics placed MPP2 at the PSD periphery and identified GABA-A receptor subunits as novel interactors, with electrophysiology demonstrating that MPP2 levels influence inhibitory synaptic currents—establishing MPP2 as a bridge between excitatory and inhibitory synaptic machinery within single spines.

   Evidence STED/STORM imaging, AP-MS quantitative proteomics, and patch-clamp electrophysiology upon MPP2 manipulation

   PMID:35312684

   Open questions at the time

   • Direct binding between MPP2 and specific GABA-A subunits not demonstrated with purified proteins
   • Whether MPP2 loss phenocopies in vivo inhibitory synapse dysfunction is untested
4. 2022 Medium

   In cerebellar granule cells, MPP2 was found to complex with CADM1, CASK, Lin7, and M-cadherin at excitatory postsynaptic regions and adherens junctions; loss of MPP2 disrupted Lin7 targeting to synaptic membranes, revealing MPP2 as an essential organizer of this multi-protein complex.

   Evidence Confocal Airyscan superresolution imaging, co-immunoprecipitation, and comparison of wild-type versus MPP2-deficient mouse cerebella

   PMID:35854144

   Open questions at the time

   • Electrophysiological or behavioral consequences of disrupted Lin7 localization in MPP2-deficient mice not assessed
   • Whether the CADM1/CASK/Lin7 complex exists at non-cerebellar synapses with MPP2 is unknown
   • Single-lab study
5. 2023 Medium

   MPP2 was linked to SK2 potassium channel trafficking at basolateral amygdala synapses, where it increases synaptic SK2 during fear extinction, thereby restoring the afterhyperpolarization current and facilitating extinction learning—connecting MPP2 scaffolding to behavioral-level neuronal excitability.

   Evidence Co-immunoprecipitation, patch-clamp electrophysiology measuring IAHP and excitability, and fear conditioning/extinction behavioral assay in mice

   PMID:37469037

   Open questions at the time

   • Direct binding domain on MPP2 responsible for SK2 interaction not mapped
   • Single-lab study without independent replication
   • Whether MPP2–SK2 interaction occurs at other brain regions is unknown
6. 2023 High

   A de novo K315N missense mutation in MPP2 was identified as a susceptibility factor for Vogt-Koyanagi-Harada uveitis, with the mutant protein gaining enhanced ANXA2 binding and activating ERK3/IL-17E inflammatory signaling, demonstrating a pathogenic gain-of-function mechanism.

   Evidence Trio-based whole-exome sequencing, CRISPR knock-in mouse model, AAV delivery, LC-MS/MS interactomics, co-immunoprecipitation, cytokine and barrier function assays, and experimental autoimmune uveitis model

   PMID:37828081

   Open questions at the time

   • Whether wild-type MPP2 normally interacts with ANXA2 at physiological levels is unclear
   • Structural basis for how K315N enhances ANXA2 binding not resolved
   • Prevalence of MPP2 mutations in broader VKH patient cohorts not established

• It remains unknown how MPP2's synaptic scaffolding functions (SynCAM1/PSD-95/GABA-A receptor/SK2 organization) are coordinately regulated, whether MPP2 undergoes post-translational modifications that switch its binding partners in different cellular contexts, and whether its epithelial c-Src regulatory role intersects with its neuronal functions.
• No structural model of full-length MPP2 or its multi-domain complexes exists
• Post-translational regulation of MPP2 is unexplored
• Comprehensive in vivo phenotyping of MPP2 knockout beyond cerebellum is lacking