SSR2

SSR2 (beta-signal sequence receptor / TRAPB) is a ubiquitously expressed endoplasmic reticulum membrane protein originally characterized as a component of the machinery for protein translocation across the ER membrane (PMID:7789174). Beyond this constitutive role, the available corpus characterizes SSR2 predominantly as a driver of tumor progression. In hepatocellular carcinoma cells, SSR2 promotes epithelial-mesenchymal transition, enhancing migration and invasion (PMID:32913453), and inhibits YAP phosphorylation to activate transcription of downstream Hippo pathway genes, conferring cisplatin resistance that is reversed by pharmacological Hippo inhibition (PMID:39206890). SSR2 also physically interacts with the ferroptosis regulator GPX4 and increases its catalytic activity, thereby suppressing ferroptosis and conferring sorafenib resistance (PMID:41568502). The pro-tumor activity of SSR2 through Hippo inactivation is also observed in lung adenocarcinoma, where SSR2 is a direct target of A-to-I edited miR-3167 (PMID:40632000). The structural basis by which SSR2 modulates YAP phosphorylation or activates GPX4 has not been reconstituted in the available corpus.

1. 1995 Medium

   Established the molecular identity of human SSR2 as an ER membrane protein linked to protein translocation, providing the baseline annotation against which later cancer roles are interpreted.

   Evidence cDNA cloning, Northern blot expression profiling, and FISH chromosomal mapping to 1q21→q23

   PMID:7789174

   Open questions at the time

   • Translocation function inferred by homology to canine beta-SSR rather than direct biochemical assay
   • No defined interaction with translocon components in human cells
   • No connection to disease at this stage
2. 2020 Medium

   Tied SSR2 to a cancer-relevant cellular phenotype by showing it is required for EMT, migration, and invasion in HCC.

   Evidence siRNA knockdown with EMT-marker Western blot and transwell migration/invasion assays in HCC cells

   PMID:32913453

   Open questions at the time

   • Molecular mechanism linking SSR2 to EMT markers not defined
   • Single lab, single tumor type
   • No in vivo confirmation of invasion phenotype
3. 2024 Medium

   Placed SSR2 upstream of the Hippo pathway by showing it suppresses YAP phosphorylation to drive downstream transcription and chemoresistance.

   Evidence Western blot, luciferase reporter, colony formation, xenograft model, and pharmacological Hippo inhibition in HCC

   PMID:39206890

   Open questions at the time

   • Direct mechanism by which SSR2 affects the kinase cascade controlling YAP phosphorylation unknown
   • No physical interaction with Hippo components shown
   • Single lab
4. 2026 Medium

   Identified a direct protein partner and a second resistance axis, showing SSR2 binds GPX4 and enhances its activity to suppress ferroptosis.

   Evidence Reciprocal Co-IP, MTT, colony formation, and ferroptosis-induction rescue in HCC cells

   PMID:41568502

   Open questions at the time

   • No in vitro reconstitution demonstrating SSR2-dependent activation of GPX4 catalysis
   • Single lab
   • Structural basis of the SSR2–GPX4 interaction unknown
5. 2025 Low

   Extended the SSR2–Hippo axis to lung adenocarcinoma and identified A-to-I edited miR-3167 as an upstream regulator that downregulates SSR2.

   Evidence Dual-luciferase reporter, RT-qPCR, Western blot, transwell, CCK-8, and flow cytometry in lung adenocarcinoma

   PMID:40632000

   Open questions at the time

   • Hippo link inferred from pathway readouts rather than directly reconstituted
   • Single lab, single study
   • Mechanism of SSR2-mediated Hippo inactivation not resolved

• How SSR2's ER translocation role mechanistically connects to its cytoplasmic regulation of YAP phosphorylation and GPX4 activity remains unresolved.
• No structural model of SSR2 in either translocation or signaling contexts
• No reconstitution of SSR2-dependent GPX4 activation or YAP regulation
• Whether the ER role and tumor signaling roles are mechanistically linked is unknown