TENM1

TENM1 (ODZ1) is a type II transmembrane protein that functions both as a regulator of tumor cell invasion and in olfactory neural connectivity (PMID:27641332, PMID:27040985). In glioblastoma stem-like cells, TENM1 is cleaved by signal peptide peptidase-like 2a (SPPL2a) upon differentiation, releasing an intracellular fragment that translocates to the nucleus and drives cytoskeletal remodelling and invasion in vitro and in vivo (PMID:27641332). The nuclear fragment activates a Myc-dependent E-box transcriptional program that upregulates RhoA expression and activity, which in turn activates ROCK to promote invasion (PMID:27641332). TENM1 transcription is induced by HIF2α under hypoxia through defined HIF consensus sites in its promoter (PMID:35054927), and it is directly repressed by miR-486 binding to its 3′UTR, with miR-486 restoration suppressing proliferation, invasion, and migration via ERK/Akt signaling and EMT in papillary thyroid carcinoma (PMID:31646573). In vivo, Tenm1 knockout and point-mutant mice display altered odor localization and aversive odor sensing, consistent with a role in olfactory synaptic partner-matching (PMID:27040985).

1. 2016 High

   Established that TENM1 is not merely a transmembrane protein but a regulated proteolytic substrate whose cleaved intracellular fragment acts in the nucleus to drive glioblastoma invasion.

   Evidence Cleavage assay, nuclear fractionation, invasion assay, xenograft, with siRNA knockdown and gene deletion in GBM stem-like cells

   PMID:27641332

   Open questions at the time

   • Precise cleavage site and topology of the released fragment not mapped
   • Whether SPPL2a cleavage operates outside GBM is unknown
2. 2016 High

   Placed the TENM1 nuclear fragment within a defined transcriptional cascade, explaining how it mechanistically converts to a pro-invasive signal.

   Evidence Epistasis by knockdown/overexpression, transcriptional reporter, Western blot, invasion assay (Myc→RhoA→ROCK)

   PMID:27641332

   Open questions at the time

   • Direct DNA binding of the fragment vs. cofactor role with Myc not resolved
   • Whether the fragment directly contacts the RhoA promoter is unknown
3. 2016 Medium

   Demonstrated a physiological neural function for TENM1 in olfaction distinct from its tumor role, linking it to synaptic partner-matching.

   Evidence CRISPR-Cas9 knockout and point-mutant mice, buried food pellet and aversive odor behavioral assays

   PMID:27040985

   Open questions at the time

   • Molecular mechanism of synaptic partner-matching not defined
   • Trans-synaptic binding partners not identified
   • Cellular site of action in the olfactory circuit not mapped
4. 2019 Medium

   Identified an upstream post-transcriptional repressor of TENM1, showing its expression is constrained by miR-486 in a second cancer context.

   Evidence Dual-luciferase 3′UTR reporter, qRT-PCR, Western, proliferation/invasion/migration assays, xenograft in papillary thyroid carcinoma

   PMID:31646573

   Open questions at the time

   • Whether TENM1 cleavage/nuclear signaling operates in thyroid carcinoma not tested
   • Direct contribution of TENM1 vs. other miR-486 targets to phenotype not isolated
5. 2022 Medium

   Connected the hypoxic tumor microenvironment to TENM1 by showing HIF2α directly drives its transcription, providing an inducing signal upstream of the invasion cascade.

   Evidence HIF2α siRNA knockdown, DMOG stabilization, luciferase reporter with cloned promoter and defined HIF binding sites, qRT-PCR/Western in GBM stem cells

   PMID:35054927

   Open questions at the time

   • Direct HIF2α occupancy at the identified sites (e.g. ChIP) not shown
   • Coupling between hypoxic induction and SPPL2a cleavage not established

• How the membrane-anchored, neural partner-matching function of TENM1 mechanistically relates to its proteolytically released nuclear pro-invasive function remains unresolved.
• No structural model of the protein or its cleaved fragment
• Trans-cellular binding partners not identified in the corpus
• Whether the nuclear fragment binds DNA directly is unknown