TMEM209

TMEM209 is a transmembrane nucleoporin resident at the nuclear pore complex that supports cell cycle progression and proliferation (PMID:41582553). It localizes to the nuclear pore complex and is positioned near inner nuclear membrane proteins and other nucleoporins, interacting biochemically with Nup210 through a region containing its two transmembrane domains; its depletion impairs cell growth and delays entry into the S, G2, and M phases, while its overexpression dissociates Nup210 from the nuclear envelope (PMID:41582553). In cancer contexts, TMEM209 drives growth through additional partners: it stabilizes the nucleoporin NUP205 and elevates nuclear c-Myc to promote lung cancer cell growth (PMID:22719065), and it binds the nuclear import protein KPNB1 to competitively block KPNB1's interaction with the E3 ligase RCHY1, preventing K48-linked ubiquitination and proteasomal degradation of KPNB1 and thereby activating Wnt/β-catenin signaling to promote hepatocellular carcinoma proliferation, migration, invasion, EMT, and metastasis (PMID:39414762). Beyond these interactions, the structural role of TMEM209 within the pore and the mechanism coupling it to cell cycle timing have not been further characterized in the available corpus.

1. 2012 Medium

   Established TMEM209 as a growth-promoting nuclear envelope protein and identified its first molecular partner, linking it to nucleoporin biology and c-Myc.

   Evidence Co-immunoprecipitation/mass spectrometry, immunofluorescence localization, and overexpression/knockdown with growth readouts in lung cancer cells

   PMID:22719065

   Open questions at the time

   • Mechanism by which NUP205 stabilization raises nuclear c-Myc not resolved
   • Whether TMEM209 is a bona fide nucleoporin not yet established at this stage
   • No structural or domain-level interaction mapping
2. 2024 Medium

   Defined a distinct oncogenic mechanism in which TMEM209 stabilizes a nuclear import factor by shielding it from ubiquitination, connecting it to Wnt/β-catenin signaling.

   Evidence Co-IP, ubiquitination and competitive interaction assays, and knockdown with in vitro and xenograft readouts in HCC

   PMID:39414762

   Open questions at the time

   • Structural basis of competitive KPNB1/RCHY1 binding not determined
   • Single-lab study without reciprocal independent validation
   • Relationship between this cytoplasmic/import role and the NPC-resident role unclear
3. 2026 High

   Resolved TMEM209's core identity as a fourth transmembrane nucleoporin at the nuclear pore complex with a defined Nup210 interaction and a cell cycle progression function.

   Evidence BioID proximity labeling, immunofluorescence, co-IP with transmembrane-domain mapping, and siRNA depletion with flow cytometry cell cycle analysis

   PMID:41582553

   Open questions at the time

   • Functional consequence of TMEM209-driven Nup210 dissociation not defined
   • Mechanism coupling NPC residence to S/G2/M timing unknown
   • No structural model of TMEM209 within the pore

• How the NPC-structural role of TMEM209 mechanistically integrates with its cancer-context stabilization of NUP205/c-Myc and KPNB1/Wnt signaling remains unresolved.
• No unified model linking pore residence to oncogenic signaling outputs
• No structural data on the transmembrane-domain interactions
• Tissue/context determinants of which partner program dominates unknown