MINAR1

MINAR1 is a single-pass transmembrane protein with a large, largely intrinsically disordered extracellular domain that functions as a negative regulator of cell growth and neuronal excitability through modulation of multiple signaling pathways. MINAR1 inhibits mTOR signaling by stabilizing the mTOR complex component DEPTOR, suppressing cell growth and colony formation, and its loss leads to mTOR hyperactivation, increased seizure susceptibility, and enhanced neuronal activity in zebrafish (PMID:30080879, PMID:34309811). MINAR1 physically interacts with Notch2 to increase its stability and negatively regulates angiogenesis in cell culture, mouse, and zebrafish models, and its re-expression in breast cancer cells inhibits tumor growth (PMID:29329397). In the mammalian brain, MINAR1 is expressed in SST+ and PV+ interneurons where it maintains Gαs-cAMP signaling and SST+ interneuron excitability; conditional knockout increases seizure susceptibility through reduced inhibitory drive onto pyramidal neurons, a defect rescued by adenylate cyclase activation (PMID:41640244).

1. 2018 Medium

   The first functional characterization established MINAR1 as a novel transmembrane protein that physically binds Notch2 to stabilize it and acts as a negative regulator of angiogenesis and tumor growth, answering what this previously uncharacterized gene does at the cellular level.

   Evidence Co-immunoprecipitation, angiogenesis assays in cell culture, mouse Matrigel plugs, zebrafish, and breast cancer xenograft models

   PMID:29329397

   Open questions at the time

   • Notch2 binding domain on MINAR1 not mapped
   • No independent replication of the Notch2 interaction
   • Mechanism by which MINAR1 binding stabilizes Notch2 is unknown
2. 2018 Medium

   An independent study identified the MINAR1 ortholog (UBTOR) as an inhibitor of mTOR signaling through stabilization of DEPTOR, providing a second major signaling axis and establishing that MINAR1 loss promotes cell growth and neurite outgrowth.

   Evidence siRNA knockdown and overexpression in mammalian cells, zebrafish ubtor knockout, xenograft mouse model, Western blot for mTOR pathway components

   PMID:30080879

   Open questions at the time

   • Whether DEPTOR stabilization is direct or indirect is not resolved
   • Relationship between the Notch2 and mTOR regulatory functions is unclear
   • Mechanism of DEPTOR stabilization (e.g., preventing ubiquitination) not dissected
3. 2021 Medium

   Zebrafish ubtor knockout demonstrated that mTOR hyperactivation downstream of MINAR1 loss causes neuronal hyperexcitability and seizure susceptibility, rescued by rapamycin, establishing a neurological consequence of the mTOR regulatory axis.

   Evidence Zebrafish knockout, spinal interneuron activity recording, PTZ seizure assay, rapamycin rescue

   PMID:34309811

   Open questions at the time

   • Cell-type specificity of MINAR1 function in the nervous system not yet addressed
   • Whether mammalian neurons show the same mTOR-dependent seizure phenotype is untested
   • Downstream effectors of mTOR mediating hyperexcitability not identified
4. 2021 Medium

   A genome-wide CRISPR screen identified MINAR1 as a pan-coronavirus host dependency factor linked to the autophagy pathway, expanding its functional repertoire beyond developmental signaling.

   Evidence CRISPR/Cas9 knockout screen in Huh7 cells validated across MERS-CoV, HCoV-229E, SARS-CoV, and SARS-CoV-2

   PMID:34962926

   Open questions at the time

   • Direct mechanistic role in coronavirus replication not dissected beyond autophagy pathway inference
   • Whether the proviral role depends on mTOR/DEPTOR axis or Notch2 interaction is unknown
   • Single cell line (Huh7) used for screening
5. 2026 High

   Conditional knockout in mouse brain resolved the cell-type specificity of MINAR1 function, showing it is expressed in SST+ and PV+ interneurons and maintains SST+ interneuron excitability through Gαs-cAMP signaling — a pathway distinct from the previously described mTOR axis.

   Evidence Nestin-Cre and SST-Cre conditional knockouts, electrophysiology, PTZ seizure model, Gαs Western blot, cAMP measurement, forskolin rescue

   PMID:41640244

   Open questions at the time

   • How MINAR1 maintains Gαs protein levels is mechanistically undefined
   • Whether the mTOR and Gαs-cAMP pathways represent parallel or convergent mechanisms in mammalian neurons is unresolved
   • PV+ interneuron functional consequences of MINAR1 loss not characterized

• How MINAR1 coordinates its multiple signaling functions (Notch2 stabilization, DEPTOR/mTOR inhibition, Gαs-cAMP maintenance) and whether these reflect distinct domain-specific interactions or a shared mechanism remains unknown.
• No structural model of MINAR1 or its interaction interfaces exists
• Whether MINAR1's disordered extracellular domain serves as a multi-partner interaction scaffold is untested
• The autophagy-related proviral mechanism for coronaviruses has not been mechanistically dissected