NUP37

NUP37 is a structural nucleoporin of the Y-complex (Nup107-160 complex) of the nuclear pore complex, with additional signaling roles beyond nucleocytoplasmic transport. Crystallography of the S. pombe orthologue shows that Nup37 binds near the bend of the L-shaped Nup120/Nup160, stabilizing the relative orientation of its two domains and providing a docking interface for ELYS (PMID:22955883). Beyond its structural role, NUP37 interacts with YAP to enhance YAP–TEAD transcriptional signaling (PMID:29228669), with DEPDC1B to modulate PI3K/AKT signaling (PMID:37203403), and with DNMT1 to influence DNA methylation-dependent gene regulation (PMID:39174498); its protein stability is controlled by TRIM28-mediated SUMOylation at Lys114/118/246, which prevents K27-linked ubiquitination and proteasomal degradation (PMID:39294431). NUP37 transcription is directly repressed by ASCL1 during neuronal differentiation, thereby reducing nuclear pore complex levels and nuclear size (PMID:41759523).

1. 2012 High

   Determining how Nup37 integrates into the Y-complex resolved a key architectural question: Nup37 binds the bend of Nup120, stabilizing inter-domain geometry and providing a composite surface for ELYS recruitment.

   Evidence X-ray crystallography of S. pombe Nup37–Nup120 complex with in vitro reconstitution and mutagenesis

   PMID:22955883

   Open questions at the time

   • Structure determined in S. pombe; human Nup37–Nup160 interface not crystallized
   • How Nup37 contributes to overall NPC assembly dynamics in vivo remains unresolved
   • No structure for the full Y-complex heptamer with Nup37 in place
2. 2017 Medium

   The discovery that NUP37 interacts with YAP and enhances YAP–TEAD binding established that NUP37 has signaling functions independent of its canonical role as a nucleoporin scaffold.

   Evidence Co-immunoprecipitation and knockdown/overexpression with proliferation, migration, and invasion assays in hepatocellular carcinoma cells

   PMID:29228669

   Open questions at the time

   • Single Co-IP without reciprocal validation or domain mapping for the NUP37–YAP interface
   • Whether the interaction occurs at the NPC or in the nucleoplasm/cytosol is unknown
   • No reconstitution of a NUP37–YAP–TEAD ternary complex
3. 2023 Medium

   Identifying DEPDC1B as a physical partner of NUP37 that signals through PI3K/AKT expanded the repertoire of NUP37-mediated signaling pathways and showed epistatic dependence of DEPDC1B on NUP37.

   Evidence Co-immunoprecipitation and epistasis rescue (NUP37 overexpression rescuing DEPDC1B knockdown) with PI3K/AKT pathway western blots in colorectal cancer cells

   PMID:37203403

   Open questions at the time

   • Direct versus indirect nature of the NUP37–PI3K/AKT link is unresolved
   • No identification of the NUP37 domain mediating DEPDC1B binding
   • Single-lab finding not independently replicated
4. 2024 Medium

   Demonstrating TRIM28-mediated SUMOylation at specific lysines that antagonizes K27-linked ubiquitination resolved how NUP37 protein levels are post-translationally regulated, linking NUP37 stability to lipid metabolism in hepatocellular carcinoma.

   Evidence SUMOylation site mapping (Lys114/118/246), ubiquitination assays, stability measurements, and TRIM28 knockdown with lipid synthesis and tumor growth readouts

   PMID:39294431

   Open questions at the time

   • The E3 ubiquitin ligase responsible for K27-linked polyubiquitination of NUP37 is unidentified
   • Whether SUMOylation of NUP37 affects its incorporation into the NPC is untested
   • Mechanism linking NUP37 protein levels to lipid biosynthesis gene expression is unclear
5. 2024 Low

   Finding that NUP37 interacts with DNMT1 and that DNMT1 overexpression rescues NUP37-depletion phenotypes suggested a role for NUP37 in epigenetic regulation through DNA methylation.

   Evidence Co-immunoprecipitation and epistasis rescue in glioma cell lines with proliferation and invasion assays

   PMID:39174498

   Open questions at the time

   • Single Co-IP in one lab without reciprocal validation or domain mapping
   • No identification of specific genomic loci whose methylation depends on the NUP37–DNMT1 interaction
   • Whether NUP37 directly modulates DNMT1 enzymatic activity or simply scaffolds it is unknown
6. 2026 Medium

   Showing that ASCL1 directly represses NUP37 transcription to reduce NPC density and nuclear size during neuronal differentiation established NUP37 as a transcriptional target linking cell-fate determination to nuclear architecture.

   Evidence ChIP demonstrating ASCL1 binding at NUP37 promoter, bidirectional genetic manipulation (knockdown and overexpression) with nuclear size and transdifferentiation readouts in fibroblast-to-neuron conversion

   PMID:41759523

   Open questions at the time

   • Whether NUP37 repression affects NPC composition globally or selectively is unexplored
   • The downstream gene-transport consequences of reduced NUP37/NPC levels in neurons are undefined
   • Whether other Y-complex subunits are co-regulated by ASCL1 is not addressed

• A unified model explaining how NUP37's structural role at the NPC relates to its multiple non-canonical signaling interactions (YAP, DEPDC1B, DNMT1) — whether these occur at the pore or via a free cytoplasmic/nuclear pool — remains unestablished.
• No quantification of NPC-incorporated versus free NUP37 pools
• No structural data for human NUP37 in complex with any signaling partner
• No loss-of-function genetics in animal models to define physiological versus cancer-context roles