TMEM98

TMEM98 is a transmembrane protein that functions as a negative regulator of the transcription factor MYRF and modulates Wnt/β-catenin and AKT/GSK3β signalling in multiple tissue contexts. TMEM98 physically binds the C-terminal fragment of MYRF at the endoplasmic reticulum, blocking MYRF autoproteolytic self-cleavage and preventing its N-terminal fragment from translocating to the nucleus to activate myelin gene transcription; conditional loss of Tmem98 in retinal pigment epithelium causes ectopic MYRF activation and nanophthalmos-like eye enlargement (PMID:30249802, PMID:32236127). TMEM98 also interacts with the GSK3-binding protein FRAT2, reducing FRAT2 levels and thereby inhibiting β-catenin/TCF signalling (PMID:31961879), and promotes endothelial cell adhesion molecule expression and vascular smooth muscle cell proliferation through the AKT/GSK3β/Cyclin D1 axis (PMID:29152140, PMID:32893666). Independently of its protein product, the TMEM98 mRNA stabilizes NF90 via a specific 8-nucleotide motif, promoting gastric cancer cell proliferation (PMID:32379372).

1. 2015 Low

   Initial loss-of-function studies established that TMEM98 supports cancer cell proliferation and invasion, but the downstream mechanism was undefined.

   Evidence siRNA knockdown in lung cancer lines with readouts for MMP-2, MMP-9, RhoC, MTA1

   PMID:26884835

   Open questions at the time

   • Single knockdown approach without epistasis or rescue experiments
   • No direct molecular target or pathway identified
   • Not independently replicated
2. 2017 Medium

   Pathway analysis placed TMEM98 upstream of AKT/GSK3β/Cyclin D1 signalling in vascular smooth muscle cells and identified a role in endothelial adhesion via ICAM-1, providing the first signalling pathway context.

   Evidence siRNA knockdown in HUVECs and VSMCs with AKT agonist rescue experiment

   PMID:29152140

   Open questions at the time

   • Knockdown-only approach; no structural or reconstitution data
   • Mechanism by which TMEM98 activates AKT is unknown
   • No direct binding partner identified in this pathway
3. 2018 High

   The central molecular function of TMEM98 was defined: it binds the C-terminal fragment of MYRF at the ER, blocks MYRF autoproteolytic self-cleavage, and prevents the N-fragment from entering the nucleus to activate myelin genes, thus acting as a stoichiometric inhibitor of oligodendrocyte differentiation.

   Evidence Co-immunoprecipitation, forced expression in embryonic chicken spinal cord, Western blot for cleavage products, immunofluorescence for nuclear translocation

   PMID:30249802

   Open questions at the time

   • Binding interface between TMEM98 and MYRF not mapped
   • Physiological regulation of TMEM98 expression during myelination not established
   • No in vivo mammalian loss-of-function at this point
4. 2020 High

   In vivo conditional knockout of Tmem98 in RPE confirmed the MYRF-inhibitory mechanism in a second tissue and revealed that unrestrained MYRF activation causes pathological eye enlargement, establishing TMEM98 as essential for ocular size control.

   Evidence Conditional KO in mouse RPE, BioID proximity labelling, immunofluorescence for MYRF nuclear localization, ocular phenotyping

   PMID:32236127

   Open questions at the time

   • Whether TMEM98 nanophthalmos mutations (A193P, H196P, R201P) act via the same MYRF derepression mechanism is not functionally demonstrated
   • Downstream MYRF target genes in RPE not fully catalogued
5. 2020 Medium

   A parallel signalling axis was revealed: TMEM98 binds FRAT2, reduces its protein levels, and thereby suppresses Wnt/β-catenin/TCF signalling, while trafficking between the plasma membrane and Golgi.

   Evidence Co-immunoprecipitation, β-catenin/TCF reporter assay, fluorescence imaging of PM–Golgi cycling

   PMID:31961879

   Open questions at the time

   • Mechanism by which TMEM98 reduces FRAT2 levels (degradation vs. sequestration) is unknown
   • Physiological context for TMEM98-FRAT2 interaction not defined in vivo
   • Relationship between Wnt pathway inhibition and MYRF regulation is unclear
6. 2020 Medium

   An RNA-level function was uncovered: TMEM98 mRNA, independently of its encoded protein, binds and stabilizes NF90 through a specific 8-nucleotide motif, promoting gastric cancer cell proliferation.

   Evidence RIP, RNA pull-down with WT and motif-mutant TMEM98 transcripts, siRNA knockdown

   PMID:32379372

   Open questions at the time

   • Whether the mRNA–NF90 interaction operates in non-cancerous contexts is unknown
   • Relative contribution of TMEM98 mRNA versus protein functions to cell proliferation not dissected
7. 2020 Medium

   TMEM98 was shown to be secreted and to sustain a positive feedback loop with PDGF-BB, activating ERK and AKT/GSK3β signalling to promote VSMC proliferation and endothelial adhesion molecule expression.

   Evidence Overexpression and siRNA knockdown, ELISA for PDGF-BB, Western blot for adhesion molecules and signalling intermediates

   PMID:32893666

   Open questions at the time

   • Secretion mechanism not defined (classical vs. non-classical pathway)
   • Receptor for secreted TMEM98 unknown
   • Relationship to the ER-resident MYRF-inhibitory pool not clarified
8. 2021 Low

   A homology model provided the first structural framework for TMEM98, localizing three nanophthalmos-causing proline substitutions (A193P, H196P, R201P) to a charge-polarized C-terminal helix (α8), suggesting this region is critical for function.

   Evidence Computational homology modelling with in vitro confirmation of transmembrane domains

   PMID:33596443

   Open questions at the time

   • No experimental structure (X-ray, cryo-EM, or NMR) available
   • Functional impact of α8 mutations on MYRF binding not tested by mutagenesis
   • Model awaits independent structural validation

• Key unresolved questions include: the structural basis of TMEM98–MYRF interaction, whether nanophthalmos mutations disrupt MYRF inhibition, how TMEM98's ER-resident and secreted pools are regulated, and whether TMEM98's multiple signalling roles (MYRF, Wnt, AKT) are integrated or context-dependent.
• No experimental structure of TMEM98 or TMEM98–MYRF complex
• Functional consequence of disease mutations on MYRF cleavage inhibition not tested
• Mechanism of TMEM98 secretion and identity of its extracellular receptor unknown