{"gene":"PRRC2C","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2023,"finding":"PRRC2C (and paralogs PRRC2A/PRRC2B) binds eukaryotic translation initiation factors and preinitiation complexes, is enriched on ribosomes translating mRNAs with upstream open reading frames (uORFs), and promotes leaky scanning past translation start codons, thereby facilitating translation of uORF-containing mRNAs.","method":"Ribosome/initiation factor binding assays, enrichment on preinitiation complexes, functional leaky scanning assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding to initiation factors demonstrated, functional leaky scanning assay performed, single lab with two orthogonal methods","pmids":["36869665"],"is_preprint":false},{"year":2026,"finding":"PRRC2C is a stress granule protein that associates with the 48S translation initiation complex (PIC) via an α-helix within its putative coiled-coil domain that interacts with the eIF3 core complex; AlphaFold3 modeling places this helix in a previously unassigned region of a published cryo-EM density map, validating the interaction. PRRC2C and its paralogs are collectively required for cell growth and influence stress granule assembly, with reduced PRRC2 proteins causing significant reduction in abundance of more than half the proteome, biased toward translational targets of eIF3d and eIF4G2.","method":"Functional proteomics (interaction domain mapping), AlphaFold3 structural modeling validated against cryo-EM density, genetic perturbation (knockdown), stress granule assembly assays, proteome abundance measurements","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — structural modeling validated by cryo-EM, interaction domain mapping, and functional perturbation in single preprint lab; multiple orthogonal methods but not yet peer-reviewed","pmids":["41808986"],"is_preprint":true},{"year":2013,"finding":"PRRC2C undergoes alternative splicing regulated by the oncogenic splicing factor SRSF1; SRSF1 downregulation leads to skipping of a PRRC2C exon that is overexpressed in primary lung tumors. Specific siRNA knockdown of the exon-containing variant significantly reduced cell growth in lung cancer cells.","method":"Exon microarray profiling, PCR-based validation, siRNA knockdown with cell growth assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated in multiple cell lines with orthogonal methods (microarray + PCR + siRNA growth assay), single lab","pmids":["24371231"],"is_preprint":false},{"year":2023,"finding":"PRRC2C knockdown in hepatocellular carcinoma cells suppresses proliferation, increases apoptosis, inhibits migration and invasion, reduces tumor formation in nude mice, and decreases expression of EMT-related proteins N-cadherin and Vimentin, indicating PRRC2C promotes HCC cell proliferation and metastasis at least partly through upregulation of EMT markers.","method":"siRNA knockdown, cell proliferation assays (Celigo, MTT, clone formation), flow cytometry (apoptosis), wound healing and Transwell invasion assays, xenograft mouse model, Western blot for EMT markers","journal":"Journal of gastrointestinal oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple orthogonal cellular and in vivo readouts, single lab","pmids":["36915448"],"is_preprint":false},{"year":2007,"finding":"PRRC2C (then called XTP2) was identified as a candidate interacting protein of HiNF-P (a histone H4 gene transcriptional regulator) in a yeast two-hybrid screen, suggesting a potential role in cell cycle regulation alongside HiNF-P.","method":"Yeast two-hybrid screen","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid screen with no functional follow-up on PRRC2C specifically","pmids":["17577209"],"is_preprint":false},{"year":2022,"finding":"PRRC2C was identified as a phosphoprotein specific to ErbB2 signaling in ovarian cancer cells (SKOV-3), detected by mass spectrometry using ErbB2 inhibitors Lapatinib and CP724714.","method":"Mass spectrometry-based phosphoproteomics with ErbB2 inhibitor treatment","journal":"Biochimica et biophysica acta. Proteins and proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single mass spectrometry identification with no mechanistic follow-up on PRRC2C specifically","pmids":["35158093"],"is_preprint":false}],"current_model":"PRRC2C is a large, intrinsically disordered stress granule protein that promotes translation initiation by binding the eIF3 core complex and the 48S preinitiation complex via an α-helical coiled-coil domain, facilitating leaky scanning past uORF start codons to enhance translation of uORF-containing mRNAs; it also undergoes SRSF1-regulated alternative splicing linked to cell growth, and its expression promotes cancer cell proliferation and EMT-associated metastasis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2007,"claim":"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","pmids":["17577209"],"confidence":"Low","gaps":["Single yeast two-hybrid hit with no functional follow-up on PRRC2C","No demonstration the interaction occurs in cells","No mechanistic role established"]},{"year":2013,"claim":"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","pmids":["24371231"],"confidence":"Medium","gaps":["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"]},{"year":2022,"claim":"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","pmids":["35158093"],"confidence":"Low","gaps":["Single MS identification with no follow-up","Phosphosites and responsible kinase not assigned","Functional consequence of phosphorylation unknown"]},{"year":2023,"claim":"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","pmids":["36869665"],"confidence":"Medium","gaps":["Direct binding interface not mapped at residue level","Scope of regulated mRNA targets not fully defined","Single lab with two orthogonal methods"]},{"year":2023,"claim":"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","pmids":["36915448"],"confidence":"Medium","gaps":["Causal link between translation function and EMT not established","Direct EMT target mRNAs not identified","Single lab study"]},{"year":2026,"claim":"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)","pmids":["41808986"],"confidence":"Medium","gaps":["Not yet peer-reviewed","Functional contribution of the modeled helix not tested by mutation","Mechanism distinguishing eIF3d/eIF4G2 target selectivity unresolved"]},{"year":null,"claim":"How PRRC2C's translation-initiation activity, alternative splicing regulation, and stress granule association are integrated to produce its pro-tumorigenic effects remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["EIF3","SRSF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y520","full_name":"Protein PRRC2C","aliases":["BAT2 domain-containing protein 1","HBV X-transactivated gene 2 protein","HBV XAg-transactivated protein 2","HLA-B-associated transcript 2-like 2","Proline-rich and coiled-coil-containing protein 2C"],"length_aa":2896,"mass_kda":316.9,"function":"Required for efficient formation of stress granules","subcellular_location":"Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q9Y520/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRRC2C","classification":"Not Classified","n_dependent_lines":96,"n_total_lines":1208,"dependency_fraction":0.07947019867549669},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RBM42","stoichiometry":10.0},{"gene":"DDX6","stoichiometry":4.0},{"gene":"EIF3G","stoichiometry":4.0},{"gene":"SRP19","stoichiometry":4.0},{"gene":"SRP68","stoichiometry":4.0},{"gene":"SRP72","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"ATG4B","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRRC2C","total_profiled":1310},"omim":[{"mim_id":"617373","title":"PROLINE-RICH COILED-COIL PROTEIN 2C; PRRC2C","url":"https://www.omim.org/entry/617373"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRRC2C"},"hgnc":{"alias_symbol":["KIAA1096","XTP2"],"prev_symbol":["BAT2D1","BAT2L2"]},"alphafold":{"accession":"Q9Y520","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y520","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y520-3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y520-3-F1-predicted_aligned_error_v6.png","plddt_mean":37.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRRC2C","jax_strain_url":"https://www.jax.org/strain/search?query=PRRC2C"},"sequence":{"accession":"Q9Y520","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y520.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y520/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y520"}},"corpus_meta":[{"pmid":"28465297","id":"PMC_28465297","title":"Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type-Specific Differences.","date":"2017","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/28465297","citation_count":109,"is_preprint":false},{"pmid":"24371231","id":"PMC_24371231","title":"Identification of alternative splicing events regulated by the oncogenic factor SRSF1 in lung cancer.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24371231","citation_count":69,"is_preprint":false},{"pmid":"36869665","id":"PMC_36869665","title":"PRRC2 proteins impact translation initiation by promoting leaky scanning.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36869665","citation_count":25,"is_preprint":false},{"pmid":"17577209","id":"PMC_17577209","title":"The interactome of the histone gene regulatory factor HiNF-P suggests novel cell cycle related roles in transcriptional control and RNA processing.","date":"2007","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17577209","citation_count":20,"is_preprint":false},{"pmid":"29270391","id":"PMC_29270391","title":"Differentially Regulated Host Proteins Associated with Chronic Rhinosinusitis Are Correlated with the Sinonasal Microbiome.","date":"2017","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29270391","citation_count":19,"is_preprint":false},{"pmid":"12443540","id":"PMC_12443540","title":"KIAA1096, a gene on chromosome 1q, is amplified and overexpressed in bladder cancer.","date":"2002","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12443540","citation_count":17,"is_preprint":false},{"pmid":"35158093","id":"PMC_35158093","title":"Phosphoproteome of signaling by ErbB2 in ovarian cancer cells.","date":"2022","source":"Biochimica et biophysica acta. Proteins and proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/35158093","citation_count":7,"is_preprint":false},{"pmid":"36915448","id":"PMC_36915448","title":"Silencing proline-rich coiled-coil 2C inhibit the proliferation and metastasis of liver cancer cells.","date":"2023","source":"Journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36915448","citation_count":3,"is_preprint":false},{"pmid":"37463531","id":"PMC_37463531","title":"Safety and efficacy of atezolizumab in Chinese patients with previously treated locally advanced or metastatic non-small cell lung cancer: An open-label, single-arm, multicenter study.","date":"2023","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/37463531","citation_count":3,"is_preprint":false},{"pmid":"36920900","id":"PMC_36920900","title":"Whole exome sequencing study identifies candidate loss of function variants and locus heterogeneity in familial cholesteatoma.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/36920900","citation_count":3,"is_preprint":false},{"pmid":"39432302","id":"PMC_39432302","title":"Construction of competitive endogenous RNA network and identification of potential regulatory axis in vascular calcification.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/39432302","citation_count":2,"is_preprint":false},{"pmid":"41808986","id":"PMC_41808986","title":"PRRC2A, PRRC2B and PRRC2C are Stress Granule Proteins that Promote Translation Through Association with the eIF3 complex.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41808986","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.02.25328820","title":"Whole-genome sequencing study of 488,888 individuals identifies rare variants and genes associated with glaucoma","date":"2025-06-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.02.25328820","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9405,"output_tokens":1535,"usd":0.02562,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8316,"output_tokens":2250,"usd":0.048915,"stage2_stop_reason":"end_turn"},"total_usd":0.074535,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"PRRC2C (and paralogs PRRC2A/PRRC2B) binds eukaryotic translation initiation factors and preinitiation complexes, is enriched on ribosomes translating mRNAs with upstream open reading frames (uORFs), and promotes leaky scanning past translation start codons, thereby facilitating translation of uORF-containing mRNAs.\",\n      \"method\": \"Ribosome/initiation factor binding assays, enrichment on preinitiation complexes, functional leaky scanning assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding to initiation factors demonstrated, functional leaky scanning assay performed, single lab with two orthogonal methods\",\n      \"pmids\": [\"36869665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PRRC2C is a stress granule protein that associates with the 48S translation initiation complex (PIC) via an α-helix within its putative coiled-coil domain that interacts with the eIF3 core complex; AlphaFold3 modeling places this helix in a previously unassigned region of a published cryo-EM density map, validating the interaction. PRRC2C and its paralogs are collectively required for cell growth and influence stress granule assembly, with reduced PRRC2 proteins causing significant reduction in abundance of more than half the proteome, biased toward translational targets of eIF3d and eIF4G2.\",\n      \"method\": \"Functional proteomics (interaction domain mapping), AlphaFold3 structural modeling validated against cryo-EM density, genetic perturbation (knockdown), stress granule assembly assays, proteome abundance measurements\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structural modeling validated by cryo-EM, interaction domain mapping, and functional perturbation in single preprint lab; multiple orthogonal methods but not yet peer-reviewed\",\n      \"pmids\": [\"41808986\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRRC2C undergoes alternative splicing regulated by the oncogenic splicing factor SRSF1; SRSF1 downregulation leads to skipping of a PRRC2C exon that is overexpressed in primary lung tumors. Specific siRNA knockdown of the exon-containing variant significantly reduced cell growth in lung cancer cells.\",\n      \"method\": \"Exon microarray profiling, PCR-based validation, siRNA knockdown with cell growth assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated in multiple cell lines with orthogonal methods (microarray + PCR + siRNA growth assay), single lab\",\n      \"pmids\": [\"24371231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRRC2C knockdown in hepatocellular carcinoma cells suppresses proliferation, increases apoptosis, inhibits migration and invasion, reduces tumor formation in nude mice, and decreases expression of EMT-related proteins N-cadherin and Vimentin, indicating PRRC2C promotes HCC cell proliferation and metastasis at least partly through upregulation of EMT markers.\",\n      \"method\": \"siRNA knockdown, cell proliferation assays (Celigo, MTT, clone formation), flow cytometry (apoptosis), wound healing and Transwell invasion assays, xenograft mouse model, Western blot for EMT markers\",\n      \"journal\": \"Journal of gastrointestinal oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple orthogonal cellular and in vivo readouts, single lab\",\n      \"pmids\": [\"36915448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PRRC2C (then called XTP2) was identified as a candidate interacting protein of HiNF-P (a histone H4 gene transcriptional regulator) in a yeast two-hybrid screen, suggesting a potential role in cell cycle regulation alongside HiNF-P.\",\n      \"method\": \"Yeast two-hybrid screen\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid screen with no functional follow-up on PRRC2C specifically\",\n      \"pmids\": [\"17577209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRRC2C was identified as a phosphoprotein specific to ErbB2 signaling in ovarian cancer cells (SKOV-3), detected by mass spectrometry using ErbB2 inhibitors Lapatinib and CP724714.\",\n      \"method\": \"Mass spectrometry-based phosphoproteomics with ErbB2 inhibitor treatment\",\n      \"journal\": \"Biochimica et biophysica acta. Proteins and proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single mass spectrometry identification with no mechanistic follow-up on PRRC2C specifically\",\n      \"pmids\": [\"35158093\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRRC2C is a large, intrinsically disordered stress granule protein that promotes translation initiation by binding the eIF3 core complex and the 48S preinitiation complex via an α-helical coiled-coil domain, facilitating leaky scanning past uORF start codons to enhance translation of uORF-containing mRNAs; it also undergoes SRSF1-regulated alternative splicing linked to cell growth, and its expression promotes cancer cell proliferation and EMT-associated metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRRC2C is a large, intrinsically disordered protein that acts at the translation initiation step to control the synthesis of specific mRNAs [#0]. 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 [#0]. PRRC2C associates with the 48S preinitiation complex through an \\u03b1-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 [#1]. PRRC2C is itself subject to SRSF1-regulated alternative splicing, with a tumor-overexpressed exon-containing variant supporting cancer cell growth [#2], and PRRC2C expression promotes hepatocellular carcinoma proliferation, survival, and metastasis in part through upregulation of the EMT markers N-cadherin and Vimentin [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid screen against the histone H4 transcriptional regulator HiNF-P\",\n      \"pmids\": [\"17577209\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single yeast two-hybrid hit with no functional follow-up on PRRC2C\", \"No demonstration the interaction occurs in cells\", \"No mechanistic role established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying PRRC2C as an SRSF1-regulated alternatively spliced transcript connected a specific exon variant to oncogenic splicing programs and cell growth.\",\n      \"evidence\": \"Exon microarray profiling with PCR validation and siRNA knockdown growth assays in lung cancer cells\",\n      \"pmids\": [\"24371231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Phosphoproteomic profiling placed PRRC2C within ErbB2 signaling, hinting at post-translational regulation, though without mechanistic resolution.\",\n      \"evidence\": \"Mass spectrometry phosphoproteomics with ErbB2 inhibitor treatment in ovarian cancer cells\",\n      \"pmids\": [\"35158093\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single MS identification with no follow-up\", \"Phosphosites and responsible kinase not assigned\", \"Functional consequence of phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Ribosome and initiation factor binding assays, enrichment on preinitiation complexes, and functional leaky scanning assays\",\n      \"pmids\": [\"36869665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface not mapped at residue level\", \"Scope of regulated mRNA targets not fully defined\", \"Single lab with two orthogonal methods\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Loss-of-function studies tied PRRC2C's molecular activity to a cancer phenotype, showing it drives HCC proliferation and metastasis with EMT-marker changes.\",\n      \"evidence\": \"siRNA knockdown with proliferation, apoptosis, migration/invasion assays, xenograft model, and Western blot for EMT markers\",\n      \"pmids\": [\"36915448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between translation function and EMT not established\", \"Direct EMT target mRNAs not identified\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Structural and proteomic work refined the mechanism, localizing the eIF3-contacting \\u03b1-helix on the 48S complex and showing PRRC2 proteins broadly sustain the proteome and stress granule assembly.\",\n      \"evidence\": \"Interaction domain mapping, AlphaFold3 modeling validated against cryo-EM density, knockdown, and proteome abundance measurements (preprint)\",\n      \"pmids\": [\"41808986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not yet peer-reviewed\", \"Functional contribution of the modeled helix not tested by mutation\", \"Mechanism distinguishing eIF3d/eIF4G2 target selectivity unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRRC2C's translation-initiation activity, alternative splicing regulation, and stress granule association are integrated to produce its pro-tumorigenic effects remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EIF3\", \"SRSF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}