PRRC2C

PRRC2C is a large, intrinsically disordered protein that acts at the translation initiation step to control the synthesis of specific mRNAs (PMID:36869665). It binds eukaryotic translation initiation factors and preinitiation complexes and is enriched on ribosomes translating mRNAs that contain upstream open reading frames (uORFs), where it promotes leaky scanning past start codons to enhance translation of uORF-containing transcripts (PMID:36869665). PRRC2C associates with the 48S preinitiation complex through an α-helix within its putative coiled-coil domain that contacts the eIF3 core complex, and depletion of PRRC2C together with its paralogs reduces the abundance of a large fraction of the proteome biased toward translational targets of eIF3d and eIF4G2, marking these proteins as collectively required for cell growth and for stress granule assembly (PMID:41808986). PRRC2C is itself subject to SRSF1-regulated alternative splicing, with a tumor-overexpressed exon-containing variant supporting cancer cell growth (PMID:24371231), and PRRC2C expression promotes hepatocellular carcinoma proliferation, survival, and metastasis in part through upregulation of the EMT markers N-cadherin and Vimentin (PMID:36915448).

1. 2007 Low

   An early protein-interaction screen first linked PRRC2C (then XTP2) to a cell-cycle context, providing the initial hint of a regulatory role before any biochemical function was known.

   Evidence Yeast two-hybrid screen against the histone H4 transcriptional regulator HiNF-P

   PMID:17577209

   Open questions at the time

   • Single yeast two-hybrid hit with no functional follow-up on PRRC2C
   • No demonstration the interaction occurs in cells
   • No mechanistic role established
2. 2013 Medium

   Identifying PRRC2C as an SRSF1-regulated alternatively spliced transcript connected a specific exon variant to oncogenic splicing programs and cell growth.

   Evidence Exon microarray profiling with PCR validation and siRNA knockdown growth assays in lung cancer cells

   PMID:24371231

   Open questions at the time

   • Functional consequence of the variant at the protein level not defined
   • Mechanism by which the exon affects growth unknown
   • Link to translation function not established
3. 2022 Low

   Phosphoproteomic profiling placed PRRC2C within ErbB2 signaling, hinting at post-translational regulation, though without mechanistic resolution.

   Evidence Mass spectrometry phosphoproteomics with ErbB2 inhibitor treatment in ovarian cancer cells

   PMID:35158093

   Open questions at the time

   • Single MS identification with no follow-up
   • Phosphosites and responsible kinase not assigned
   • Functional consequence of phosphorylation unknown
4. 2023 Medium

   Biochemical work established the first molecular function for PRRC2C: a translation initiation factor that binds preinitiation complexes and promotes leaky scanning to translate uORF-containing mRNAs.

   Evidence Ribosome and initiation factor binding assays, enrichment on preinitiation complexes, and functional leaky scanning assays

   PMID:36869665

   Open questions at the time

   • Direct binding interface not mapped at residue level
   • Scope of regulated mRNA targets not fully defined
   • Single lab with two orthogonal methods
5. 2023 Medium

   Loss-of-function studies tied PRRC2C's molecular activity to a cancer phenotype, showing it drives HCC proliferation and metastasis with EMT-marker changes.

   Evidence siRNA knockdown with proliferation, apoptosis, migration/invasion assays, xenograft model, and Western blot for EMT markers

   PMID:36915448

   Open questions at the time

   • Causal link between translation function and EMT not established
   • Direct EMT target mRNAs not identified
   • Single lab study
6. 2026 Medium

   Structural and proteomic work refined the mechanism, localizing the eIF3-contacting α-helix on the 48S complex and showing PRRC2 proteins broadly sustain the proteome and stress granule assembly.

   Evidence Interaction domain mapping, AlphaFold3 modeling validated against cryo-EM density, knockdown, and proteome abundance measurements (preprint)

   PMID:41808986

   Open questions at the time

   • Not yet peer-reviewed
   • Functional contribution of the modeled helix not tested by mutation
   • Mechanism distinguishing eIF3d/eIF4G2 target selectivity unresolved

• How PRRC2C's translation-initiation activity, alternative splicing regulation, and stress granule association are integrated to produce its pro-tumorigenic effects remains unresolved.
• No defined set of in vivo mRNA targets linking translation control to EMT
• Role of phosphorylation and splice variants in modulating the initiation function unknown
• No structural validation of the eIF3-binding helix by mutagenesis