JUP

Plakoglobin (JUP) is a desmosomal junction protein required for the integrity of skin and heart, as established by human loss-of-function and missense mutations that produce palmoplantar keratoderma, woolly hair, skin fragility, and arrhythmogenic right ventricular cardiomyopathy (PMID:20130592, PMID:21668431). Beyond its structural adhesion role, JUP behaves as a dual-compartment scaffold that shapes signaling: at the membrane and cytoplasm it restrains EGFR and thereby suppresses AKT/GSK3β/β-catenin signaling, whereas in the nucleus it complexes with β-catenin and TCF4 to drive transcription of invasion genes including MMP7, with loss of membrane JUP promoting epithelial-mesenchymal transition and invasion in gastric cancer (PMID:33364056). JUP function in adhesion-linked signaling is also coupled to the desmoglein DSG2/plakoglobin/β-catenin axis, which TROP2 disrupts to promote gastric cancer invasion (PMID:35392784). JUP abundance is controlled by K48-linked ubiquitination and proteasomal degradation through the XAF1-VCP-RNF114 E3 ligase axis, and its degradation promotes colorectal cancer migration and metastasis (PMID:38095639). JUP transcription can be induced via a non-canonical DHT/EPPK1/p38 MAPK/c-Jun pathway in bladder cancer, where c-Jun binds the JUP promoter to drive proliferation and invasion (PMID:37328487).

1. 1991 Medium

   Establishing the chromosomal location of the plakoglobin gene was the first step toward genetic characterization of the locus.

   Evidence PCR-based chromosomal assignment using human-rodent somatic cell hybrids

   PMID:1889810

   Open questions at the time

   • No functional or protein-level characterization
   • Did not define gene structure or expression
2. 2000 Medium

   Resolving the intron-exon organization of JUP provided the genomic framework needed for mutation analysis.

   Evidence Genomic cloning, sequencing, and PCR-based exon mapping

   PMID:11016852

   Open questions at the time

   • No link to disease or function at this stage
   • Regulatory elements not mapped
3. 2005 Low

   Detection of JUP mRNA in primate neurons raised the question of a role outside epithelial/cardiac junctions, though function was not tested.

   Evidence In situ hybridization in adult primate prefrontal cortex and hippocampus

   PMID:15857685

   Open questions at the time

   • Single localization method, no functional consequence tested
   • Protein-level confirmation absent
   • Neuronal role unestablished
4. 2010 High

   Human homozygous loss-of-function mutations showed plakoglobin is essential for skin integrity and that its absence need not compromise heart development, also revealing an alternative-AUG truncated protein.

   Evidence Mutation sequencing, patient skin immunostaining, and analysis of alternative translation initiation

   PMID:20130592

   Open questions at the time

   • Does not explain genotype-specific cardiac sparing mechanistically
   • Function of the truncated protein unresolved
5. 2011 Medium

   A recessive missense mutation linked JUP to a combined cardiac-cutaneous syndrome, showing specific alleles disrupt both heart and skin desmosomal function.

   Evidence Genetic mapping and mutation identification in an affected family

   PMID:21668431

   Open questions at the time

   • Single family, no molecular reconstitution
   • Mechanism of mutation effect on desmosome not defined
6. 2022 Medium

   Identification of the DSG2/plakoglobin/β-catenin axis as a TROP2 target connected JUP-linked desmosomal signaling to cancer invasion control.

   Evidence Co-IP/MS, TROP2 manipulation, invasion assays, and desmosome electron microscopy in gastric cancer cells

   PMID:35392784

   Open questions at the time

   • Direct JUP interaction with TROP2 not the focus
   • Single lab, partial JUP-specific follow-up
7. 2020 Medium

   Reciprocal functional studies defined JUP as a dual-compartment signaling switch: membrane JUP restrains EGFR/AKT signaling and suppresses EMT, while nuclear JUP/β-catenin/TCF4 drives invasion genes.

   Evidence JUP knockdown/overexpression, co-IP, and migration/invasion assays in gastric cancer cell lines

   PMID:33364056

   Open questions at the time

   • Single lab
   • Determinants of JUP nuclear versus membrane partitioning not defined
   • Direct EGFR binding not structurally resolved
8. 2023 High

   Defining the XAF1-VCP-RNF114 axis established how JUP protein abundance is post-translationally controlled and linked its degradation to metastasis.

   Evidence Reciprocal Co-IP, K48-linkage ubiquitination assays, rescue experiments, and clinical correlation in colorectal cancer

   PMID:38095639

   Open questions at the time

   • Ubiquitination site on JUP not mapped
   • Whether degradation occurs in specific subcellular pools unknown
9. 2023 Medium

   Mapping the DHT/EPPK1/p38 MAPK/c-Jun pathway showed JUP expression can be transcriptionally induced non-canonically to drive bladder cancer growth.

   Evidence Biotinylated DHT pull-down, p38 inhibition, c-Jun promoter binding, JUP knockdown, and xenografts

   PMID:37328487

   Open questions at the time

   • Direct c-Jun/JUP promoter binding shown by ChIP-like assay only
   • Generalizability beyond bladder cancer untested

• How JUP's subcellular partitioning between adhesion, cytoplasmic signaling restraint, and nuclear transcription is coordinated, and how this integrates with its tissue-specific roles in skin and heart, remains unresolved.
• No structural model connecting adhesion and signaling functions
• Mechanism partitioning JUP to nucleus versus membrane unknown
• Cardiac versus cutaneous mutation specificity unexplained