SEC11A

SEC11A encodes SPC18, a catalytic subunit of the endoplasmic reticulum signal peptidase complex, and functions in cancer biology by promoting the secretion of growth-promoting factors that drive proliferation and invasion (PMID:23995782). SPC18 promotes secretion of TGF-α, and its depletion reduces TGF-α in culture media while its overexpression enhances tumor cell growth in vitro and in vivo (PMID:23995782). Downstream of this secretory output, SPC18 acts upstream of EGFR/MAPK/PI3K signaling: its knockdown lowers phosphorylated EGFR, Erk, and Akt, and its expression at the invasive front co-localizes with nuclear β-catenin and MMP7 (PMID:27859949). SEC11A is directly repressed by miR-873-5p, and the anti-tumor effect of this microRNA proceeds through suppression of SEC11A and EGFR pathway proteins, with the phenotype rescued by SEC11A re-expression (PMID:33675129). Beyond its role in tumor cell growth and invasion across multiple cancer types (PMID:23995782, PMID:27859949), SEC11A is an essential host factor for human metapneumovirus replication, and HMPV infection specifically induces an exon-skipping splicing event in the SEC11A regulatory region upstream of its coding sequence (PMID:41743027).

1. 2013 Medium

   Established that SPC18 promotes cancer progression not merely as a housekeeping peptidase but by driving secretion of the EGFR ligand TGF-α, linking signal-peptidase activity to a specific oncogenic secreted factor.

   Evidence siRNA knockdown and overexpression with TGF-α ELISA, proliferation/invasion assays, and xenografts in gastric cancer cells

   PMID:23995782

   Open questions at the time

   • Direct enzymatic cleavage of the TGF-α signal peptide by SPC18 not biochemically reconstituted
   • Whether SPC18 selectively favors TGF-α over other secretory substrates unaddressed
   • Composition of the signal peptidase complex in these cells not characterized
2. 2017 Medium

   Placed SPC18 upstream of a defined intracellular signaling cascade by showing its loss reduces EGFR/MAPK/PI3K phosphorylation, connecting its secretory role to downstream proliferative signaling and invasive-front markers.

   Evidence siRNA knockdown with phospho-EGFR/Erk/Akt Western blots and IHC co-localization with β-catenin and MMP7 in colorectal cancer

   PMID:27859949

   Open questions at the time

   • Causal chain from SPC18 to phospho-EGFR not separated from general secretory defects
   • Identity of the secreted ligand mediating EGFR activation in CRC not established
   • Mechanism linking SPC18 to β-catenin nuclear localization unknown
3. 2021 Medium

   Identified an upstream regulatory mechanism showing SEC11A is a direct miR-873-5p target, explaining how SEC11A levels are controlled and reinforcing the SEC11A→EGFR signaling axis through rescue.

   Evidence Dual luciferase reporter, Western blot, and SEC11A-overexpression rescue in tongue squamous cell carcinoma cells

   PMID:33675129

   Open questions at the time

   • Physiological contexts in which miR-873-5p regulates SEC11A not defined
   • Whether other microRNAs co-regulate SEC11A unaddressed
   • Single-lab validation of the binding interaction
4. 2023 Low

   Extended the pro-tumor loss-of-function phenotype to HNSCC and reported predominantly cytoplasmic SPC18 localization, broadening the cancer-type generality of the secretory growth role.

   Evidence shRNA lentiviral knockdown with proliferation/migration/invasion assays, xenografts, and IHC localization in HNSCC

   PMID:37025806

   Open questions at the time

   • No new pathway mechanism identified beyond prior work
   • Secreted substrate mediating the HNSCC phenotype not identified
   • Cytoplasmic IHC signal not resolved to ER subcompartment
5. 2026 Medium

   Revealed a host-pathogen role by showing SEC11A is required for human metapneumovirus replication and that HMPV reprograms SEC11A splicing, implicating signal-peptidase function in viral biology.

   Evidence CRISPR knockout cell lines with HMPV replication readout and RNA-seq detection of an infection-induced exon-skipping event

   PMID:41743027

   Open questions at the time

   • Whether SEC11A acts by processing a viral protein or supporting host secretory machinery unknown
   • Functional consequence of the exon-skipping event on SPC18 activity not determined
   • Mechanism by which HMPV induces the splicing change uncharacterized

• The direct biochemical activity of SPC18 as the catalytic signal peptidase subunit, including its substrate repertoire and complex composition in human cells, remains uncharacterized in this corpus.
• No direct demonstration of signal-peptide cleavage by human SPC18 in the corpus
• Subunit partners of the signal peptidase complex not experimentally defined here
• ER-membrane catalytic mechanism not addressed