TMEM92

TMEM92 is a single-transmembrane protein that functions as a positive driver of breast cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) (PMID:32835947, PMID:42138474). Knockdown of TMEM92 in breast carcinoma cells suppresses viability, invasiveness, and motility and reverses EMT (raising E-cadherin while lowering N-cadherin, Vimentin, and Snail), whereas overexpression promotes these phenotypes (PMID:32835947). Mechanistically, TMEM92 directly associates with the RNA helicase DDX3X and stabilizes it: by competitively blocking the E3 ubiquitin ligase TTC3 from binding DDX3X, TMEM92 inhibits TTC3-mediated K48-linked ubiquitination and proteasomal degradation of DDX3X, and re-expression of DDX3X rescues the anti-tumor effects of TMEM92 depletion, placing TMEM92 upstream of DDX3X in a TMEM92–DDX3X–TTC3 axis that drives triple-negative breast cancer progression and cisplatin resistance (PMID:42138474).

1. 2011 Low

   Before any functional data existed, the question was what protein class TMEM92 belongs to and what it might do; sequence analysis assigned it to a transmembrane adaptor family, framing it as a candidate signaling/adaptor protein.

   Evidence Sequence similarity, pattern-based searches, and phylogenetic analysis classifying TMEM92 in the STMC6 (Shisa-like) family with PY motifs

   PMID:22120523

   Open questions at the time

   • Computational prediction only; no experimental validation of any interaction or function
   • Predicted NEDD4-family/WW-domain interaction via PY motifs never tested
   • No cellular role established
2. 2020 Medium

   The first functional question — whether TMEM92 has a role in cancer cell behavior — was answered by showing it is a positive regulator of EMT and malignant phenotypes in breast carcinoma cells.

   Evidence siRNA knockdown and overexpression in MDA-MB-231 cells with CCK-8, clone formation, Transwell, and western blot for EMT markers

   PMID:32835947

   Open questions at the time

   • No binding partner or molecular mechanism identified
   • Single cell line, single lab
   • No in vivo validation
3. 2026 High

   The mechanistic question of how TMEM92 drives tumor phenotypes was answered by identifying a direct partner, DDX3X, and a degradation-control mechanism: TMEM92 stabilizes DDX3X by competing with the E3 ligase TTC3.

   Evidence Co-IP/pulldown, ubiquitination assays, TMEM92 depletion with DDX3X rescue, xenograft models, and cisplatin IC50 measurement in TNBC

   PMID:42138474

   Open questions at the time

   • Structural basis of TMEM92–DDX3X and TMEM92/TTC3 competition not defined
   • How a transmembrane protein engages the helicase and ligase spatially is unresolved
   • Downstream effectors linking stabilized DDX3X to EMT not mapped

• It remains unknown whether the TMEM92–DDX3X–TTC3 axis operates beyond breast cancer and whether the originally predicted PY-motif/NEDD4-family interactions contribute to TMEM92 function.
• No data on TMEM92 function in normal tissues or other tumor types
• Predicted WW-domain/E3 ligase interactions remain untested
• Membrane topology and trafficking of TMEM92 not characterized