MPP3

MPP3 is a PDZ-domain scaffold protein that organizes membrane-associated multi-protein complexes at cell-cell junctions and apical membranes to maintain epithelial/neuroepithelial architecture and to couple adhesion to intracellular signaling (PMID:13679854, PMID:23658188). Through its PDZ domain it binds the C-terminal PDZ-binding motifs of transmembrane partners, directly associating with the adhesion molecule CADM1/TSLC1 at cell-cell attachment sites (PMID:13679854) and with the serotonin 5-HT2C receptor, where it stabilizes receptor surface expression and prevents desensitization of the receptor Ca2+ response (PMID:16914526). In neuroepithelia, MPP3 is recruited into the MPP5/PALS1 apical scaffold alongside CRB1 and forms separate complexes with DLG1, and it is required to maintain PALS1 levels at the retinal subapical region and the integrity of the apical junctional complex; its loss randomizes spindle orientation, produces ectopic mitoses, and disrupts cortical stratification and retinal organization (PMID:16519681, PMID:23658188, PMID:23893895). MPP3 also nucleates a CADM1–DLG–p85(PI3K) complex in which trans-homophilic CADM1 engagement activates PI3K, Akt and Rac1 to drive actin reorganization and cell spreading (PMID:24503895, PMID:25268382). In the hematopoietic system, a secretory FcγR+/ERhigh subset of myeloid-biased MPP3 progenitors amplifies myeloid output through inflammation-triggered cytokine secretion (PMID:37115584).

1. 2003 Medium

   Established that MPP3 functions as a junctional scaffold by identifying its first direct transmembrane binding partner, defining the PDZ-domain mode of interaction.

   Evidence Co-immunoprecipitation, PDZ-binding motif mutagenesis and colocalization of CADM1/TSLC1 with MPP3

   PMID:13679854

   Open questions at the time

   • Functional consequence of the CADM1-MPP3 interaction not addressed
   • Single lab, no in vivo validation
2. 2006 Medium

   Showed MPP3 has a receptor-stabilizing function distinct from other MAGUKs, regulating surface expression and signaling kinetics of a GPCR via PDZ binding.

   Evidence Calcium response and surface receptor assays in transfected cells and cortical neurons with Tat-peptide PDZ displacement

   PMID:16914526

   Open questions at the time

   • Structural basis of differential effect versus PSD-95 not defined
   • Physiological relevance of 5-HT2C regulation in vivo not tested
3. 2006 Medium

   Placed MPP3 within the apical CRB/PALS1 scaffold and showed it forms compartment-specific complexes, locating it within the apical polarity machinery.

   Evidence Immunofluorescence colocalization and in vivo Co-IP in human and mouse retina

   PMID:16519681

   Open questions at the time

   • Hierarchy of complex assembly not resolved
   • Functional requirement not tested in this study
4. 2013 High

   Demonstrated MPP3 is functionally required to maintain apical junctional and adherens complexes, linking the scaffold to spindle orientation and cortical development.

   Evidence Conditional Mpp3 knockout mouse cortex with immunostaining, spindle orientation and cell-cycle analyses

   PMID:23658188

   Open questions at the time

   • Direct molecular mechanism connecting MPP3 to spindle positioning not established
   • Which partner loss drives each phenotype unresolved
5. 2013 High

   Established MPP3 as a stabilizer of PALS1 at the apical membrane through genetic epistasis, defining a hierarchical scaffold dependency in retinal maintenance.

   Evidence Conditional Mpp3 KO with immunostaining, electroretinography and Pals1 double-mutant epistasis

   PMID:23893895

   Open questions at the time

   • Mechanism by which MPP3 stabilizes PALS1 (protection from degradation vs recruitment) not defined
6. 2014 Medium

   Connected MPP3-anchored adhesion complexes to downstream signaling, showing CADM1 engagement drives PI3K/Akt/Rac1 activation and cytoskeletal remodeling.

   Evidence Cell spreading assays with PI3K/Akt/Rac1 inhibitors and Co-IP of CADM1/MPP3/DLG/p85 complex

   PMID:24503895 PMID:25268382

   Open questions at the time

   • Direct vs indirect role of MPP3 in PI3K recruitment not separated
   • In vivo significance of the signaling axis not tested
7. 2023 Medium

   Identified a functionally distinct secretory subset of MPP3 progenitors that amplifies myeloid output, extending MPP3-associated biology to hematopoiesis.

   Evidence Flow cytometry subset identification, lineage tracing and cytokine secretion assays in inflammatory stress models

   PMID:37115584

   Open questions at the time

   • Role of the MPP3 scaffold protein itself versus the MPP3 progenitor population not disambiguated
   • Molecular link between scaffold function and secretory phenotype not established

• How MPP3 mechanistically stabilizes its partners (PALS1, surface receptors) and whether its junctional scaffolding role connects to the secretory hematopoietic progenitor biology remains unresolved.
• No structural model of MPP3 PDZ-partner complexes
• No reconstitution of the CADM1/MPP3/DLG/p85 signaling module
• Whether 'MPP3 progenitor' biology involves the scaffold gene product is unclear