{"gene":"PRR16","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2014,"finding":"PRR16 (named Largen) was identified as a regulator of mammalian cell size: overexpression increased cell size in human cells and in conditional transgenic mice, independently of mTOR and Hippo signalling pathways. Mechanistically, Largen preferentially stimulates the translation of specific subsets of mRNAs, including those encoding mitochondrial function proteins, leading to increased mitochondrial mass and greater ATP production.","method":"Genetic screen for cell-size-controlling genes; overexpression in human cells; in vitro translation assays; conditional transgenic mouse analysis; mitochondrial mass and ATP production assays","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetic screen, in vitro translation, in vivo transgenic mouse), moderate-to-strong evidence from a single rigorous study","pmids":["24656129"],"is_preprint":false},{"year":2022,"finding":"PRR16/Largen induces epithelial-mesenchymal transition (EMT) by physically binding to ABI2 (Abl interactor 2), thereby interfering with ABI2's inhibitory role on ABL1 kinase. PRR16 overexpression increased phosphorylation of ABL1 at Y412 (activation), enhanced migration and invasion in MCF7 breast cancer cells, and gene silencing of ABI2 phenocopied PRR16 overexpression by also inducing EMT and ABL1 activation.","method":"Co-immunoprecipitation/binding partner screen; gene overexpression and siRNA knockdown; ABL1 phosphorylation assay (Y412); migration and invasion assays in MCF7 cells","journal":"Biomolecules & Therapeutics","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal functional validation (OE + KD), multiple phenotypic readouts, but single lab study","pmids":["35719027"],"is_preprint":false}],"current_model":"PRR16 (Largen) controls mammalian cell size independently of mTOR/Hippo by selectively stimulating translation of mitochondrial-function mRNAs to increase mitochondrial mass and ATP production; it also promotes epithelial-mesenchymal transition by binding ABI2 and relieving its inhibition of ABL1 kinase, thereby activating ABL1-dependent migration and invasion."},"narrative":{"teleology":[{"year":2014,"claim":"The mechanism by which mammalian cells control their size outside the canonical mTOR and Hippo pathways was unknown; a genetic screen identified PRR16 (Largen) as a cell-size regulator that preferentially stimulates translation of mitochondrial-function mRNAs, increasing mitochondrial mass and ATP production.","evidence":"Genetic screen for cell-size genes, overexpression in human cells, in vitro translation assays, conditional transgenic mouse, mitochondrial mass/ATP assays","pmids":["24656129"],"confidence":"High","gaps":["The direct RNA-binding or ribosome-recruitment mechanism by which Largen selects specific mRNA subsets for translational stimulation is unresolved","No structural information for Largen or its translational regulatory domain exists","Whether Largen-dependent cell-size control operates equivalently across different tissues in vivo remains untested beyond the transgenic model"]},{"year":2022,"claim":"Whether PRR16 had roles beyond cell-size control was unclear; PRR16 was shown to bind ABI2 and relieve its inhibition of ABL1 kinase, activating ABL1 and inducing EMT-associated migration and invasion in breast cancer cells.","evidence":"Co-immunoprecipitation, overexpression and siRNA knockdown in MCF7 cells, ABL1 Y412 phosphorylation assay, migration/invasion assays","pmids":["35719027"],"confidence":"Medium","gaps":["The PRR16–ABI2 interaction has been demonstrated by Co-IP in a single study and lacks independent replication or structural mapping of the binding interface","Whether the translational and EMT-promoting functions of PRR16 are mechanistically coupled or represent independent activities is unknown","In vivo relevance of the PRR16–ABI2–ABL1 axis in tumour progression has not been tested"]},{"year":null,"claim":"The molecular basis by which PRR16 selectively enhances translation of specific mRNA subsets, and whether its translational and EMT-promoting functions converge on a shared mechanism, remain open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No RNA-binding domain or ribosome-interaction surface has been identified in PRR16","No proteome-wide or ribosome-profiling study has validated the translational selectivity in an independent system","Relationship between mitochondrial biogenesis function and ABI2/ABL1-mediated EMT induction is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":[],"partners":["ABI2","ABL1"],"other_free_text":[]},"mechanistic_narrative":"PRR16 (Largen) is a regulator of mammalian cell size that acts independently of mTOR and Hippo signalling by selectively stimulating translation of mRNAs encoding mitochondrial-function proteins, thereby increasing mitochondrial mass and ATP production [PMID:24656129]. PRR16 also promotes epithelial–mesenchymal transition (EMT) by physically binding ABI2 and relieving its inhibition of ABL1 kinase, leading to ABL1 activation (Y412 phosphorylation) and enhanced cell migration and invasion [PMID:35719027]."},"prefetch_data":{"uniprot":{"accession":"Q569H4","full_name":"Protein Largen","aliases":["Mesenchymal stem cell protein DSC54","Proline-rich protein 16"],"length_aa":304,"mass_kda":32.8,"function":"Regulator of cell size that promotes cell size increase independently of mTOR and Hippo signaling pathways. Acts by stimulating the translation of specific mRNAs, including those encoding proteins affecting mitochondrial functions. Increases mitochondrial mass and respiration","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q569H4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRR16","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PRR16","total_profiled":1310},"omim":[{"mim_id":"615931","title":"PROLINE-RICH PROTEIN 16; PRR16","url":"https://www.omim.org/entry/615931"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Midbody","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"tongue","ntpm":28.3}],"url":"https://www.proteinatlas.org/search/PRR16"},"hgnc":{"alias_symbol":["DSC54"],"prev_symbol":[]},"alphafold":{"accession":"Q569H4","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q569H4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q569H4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q569H4-F1-predicted_aligned_error_v6.png","plddt_mean":63.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRR16","jax_strain_url":"https://www.jax.org/strain/search?query=PRR16"},"sequence":{"accession":"Q569H4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q569H4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q569H4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q569H4"}},"corpus_meta":[{"pmid":"24243566","id":"PMC_24243566","title":"Maternal preconception body mass index and offspring cord blood DNA methylation: exploration of early life 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complexes.","date":"2025","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/40437099","citation_count":6,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6102,"output_tokens":754,"usd":0.014808},"stage2":{"model":"claude-opus-4-6","input_tokens":3934,"output_tokens":943,"usd":0.064867},"total_usd":0.180884,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":17268,"output_tokens":1057,"usd":0.033829},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4059,"output_tokens":985,"usd":0.06738}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"PRR16 (Largen) overexpression increases mammalian cell size in a manner independent of mTOR and Hippo signalling, acting by preferentially stimulating translation of specific subsets of mRNAs, including those encoding mitochondrial function proteins, leading to increased mitochondrial mass and greater ATP production.\",\n      \"method\": \"Genetic screen for cell-size-controlling genes; overexpression in human cells; in vitro translation assays; conditional transgenic mouse model; mitochondrial mass and ATP measurements\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vitro assay, transgenic mouse, metabolic measurements) in a single rigorous study\",\n      \"pmids\": [\"24656129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRR16/Largen binds to ABI2 (Abl interactor 2) and interferes with ABI2's inhibition of ABL1 kinase, resulting in increased ABL1 Y412 phosphorylation and induction of epithelial-mesenchymal transition (EMT), enhancing migration and invasion in breast cancer cells.\",\n      \"method\": \"Binding partner screen (Co-IP/pulldown); gene silencing of ABI2; PRR16 overexpression in MCF7 cells; phosphorylation assay (Y412 ABL1); migration and invasion assays\",\n      \"journal\": \"Biomolecules & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal interaction identified with functional follow-up, but single lab study\",\n      \"pmids\": [\"35719027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Prr16 (encoding Largen protein) was identified as a candidate causal gene for oxygen consumption in mice, consistent with its established role in mitochondrial respiration and ATP production.\",\n      \"method\": \"Selective signature detection via pooled whole-genome resequencing in divergently selected high/low oxygen consumption mouse populations\",\n      \"journal\": \"Journal of animal breeding and genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — genomic/genetic association without direct functional experiment\",\n      \"pmids\": [\"35608337\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRR16 (Largen) is a cell size regulator that preferentially stimulates translation of specific mRNA subsets (including those encoding mitochondrial proteins) to increase mitochondrial mass and ATP production, thereby enlarging mammalian cell size independently of mTOR and Hippo pathways; additionally, PRR16 binds ABI2 to relieve its inhibition of ABL1 kinase, activating ABL1 and inducing epithelial-mesenchymal transition.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEEP papers.\n\n**Classification:**\n\n- Paper [1] corpus[1] PMID:24243566 — EXCLUDE (expression/methylation association, no mechanistic finding about PRR16 protein)\n- Paper [2] corpus[2] PMID:18673379 — EXCLUDE (endothelial cell differentiation, PRR16 not studied)\n- Paper [3] corpus[3] PMID:32311840 — EXCLUDE (expression correlation/biomarker study)\n- Paper [4] corpus[4] PMID:37945807 — EXCLUDE (GWAS association study, no PRR16 mechanism)\n- Paper [5] corpus[5] PMID:24656129 — **KEEP** (directly about PRR16/Largen protein function)\n- Paper [6] corpus[6] PMID:31397435 — EXCLUDE (mutation association study, no mechanism)\n- Paper [7] corpus[7] PMID:35719027 — **KEEP** (directly about PRR16/Largen mechanism in EMT)\n- Paper [8] corpus[8] PMID:38091677 — EXCLUDE (epigenetic/methylation association)\n- Paper [9] corpus[9] PMID:35608337 — EXCLUDE (genetic/QTL study, no direct mechanistic experiment on PRR16)\n\nAdditional papers: All are large-scale interactome/proteomics screens or GWAS studies not specifically about PRR16 mechanism — EXCLUDE (none specifically characterize PRR16 mechanism; PRR16 appears only as one of thousands of proteins in proteome-wide datasets).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"PRR16 (named Largen) was identified as a regulator of mammalian cell size: overexpression increased cell size in human cells and in conditional transgenic mice, independently of mTOR and Hippo signalling pathways. Mechanistically, Largen preferentially stimulates the translation of specific subsets of mRNAs, including those encoding mitochondrial function proteins, leading to increased mitochondrial mass and greater ATP production.\",\n      \"method\": \"Genetic screen for cell-size-controlling genes; overexpression in human cells; in vitro translation assays; conditional transgenic mouse analysis; mitochondrial mass and ATP production assays\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic screen, in vitro translation, in vivo transgenic mouse), moderate-to-strong evidence from a single rigorous study\",\n      \"pmids\": [\"24656129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PRR16/Largen induces epithelial-mesenchymal transition (EMT) by physically binding to ABI2 (Abl interactor 2), thereby interfering with ABI2's inhibitory role on ABL1 kinase. PRR16 overexpression increased phosphorylation of ABL1 at Y412 (activation), enhanced migration and invasion in MCF7 breast cancer cells, and gene silencing of ABI2 phenocopied PRR16 overexpression by also inducing EMT and ABL1 activation.\",\n      \"method\": \"Co-immunoprecipitation/binding partner screen; gene overexpression and siRNA knockdown; ABL1 phosphorylation assay (Y412); migration and invasion assays in MCF7 cells\",\n      \"journal\": \"Biomolecules & Therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal functional validation (OE + KD), multiple phenotypic readouts, but single lab study\",\n      \"pmids\": [\"35719027\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRR16 (Largen) controls mammalian cell size independently of mTOR/Hippo by selectively stimulating translation of mitochondrial-function mRNAs to increase mitochondrial mass and ATP production; it also promotes epithelial-mesenchymal transition by binding ABI2 and relieving its inhibition of ABL1 kinase, thereby activating ABL1-dependent migration and invasion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PRR16 (Largen) is a cell size regulator that increases mammalian cell size independently of mTOR and Hippo signaling by preferentially stimulating translation of specific mRNA subsets, including those encoding mitochondrial proteins, thereby augmenting mitochondrial mass and ATP production [PMID:24656129]. PRR16 also binds ABI2 (Abl interactor 2), relieving ABI2-mediated inhibition of ABL1 kinase and promoting ABL1 Y412 phosphorylation, which drives epithelial–mesenchymal transition and enhances migration and invasion in breast cancer cells [PMID:35719027].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing that PRR16 controls cell size through selective translational stimulation — prior to this, no pathway-independent mechanism linking a single gene to mammalian cell size via mRNA-selective translation was known; PRR16 overexpression was shown to preferentially increase translation of mitochondrial-function mRNAs, boosting mitochondrial mass and ATP output.\",\n      \"evidence\": \"Genetic screen, overexpression in human cells, in vitro translation assays, conditional transgenic mouse model, mitochondrial mass and ATP measurements\",\n      \"pmids\": [\"24656129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The mechanism by which PRR16 selects specific mRNA subsets for enhanced translation is undefined\",\n        \"Direct RNA-binding or ribosome-association data for PRR16 are lacking\",\n        \"Whether PRR16-driven cell enlargement is relevant in vivo outside the transgenic context is not established\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealing a second functional axis — PRR16 binds ABI2 and de-represses ABL1 kinase to drive EMT, connecting a cell-size regulator to cell migration and invasion; this was previously unsuspected from the translational role.\",\n      \"evidence\": \"Co-IP/pulldown binding screen, ABI2 silencing, PRR16 overexpression in MCF7 breast cancer cells, ABL1 Y412 phosphorylation assay, migration and invasion assays\",\n      \"pmids\": [\"35719027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-laboratory study; independent confirmation of the PRR16–ABI2 interaction is needed\",\n        \"Whether the ABL1-activating and translational functions of PRR16 are mechanistically linked or independent is unknown\",\n        \"Structural basis of the PRR16–ABI2 interaction has not been determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis of PRR16's mRNA selectivity, its direct RNA or ribosome contacts, and whether its translational and ABL1-activating functions converge in a unified physiological process remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of PRR16 exists\",\n        \"No direct RNA-binding or ribosome-interaction data have been reported\",\n        \"Physiological integration of the two described functions (translation regulation and ABL1 activation) has not been tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ABI2\", \"ABL1\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PRR16 (Largen) is a regulator of mammalian cell size that acts independently of mTOR and Hippo signalling by selectively stimulating translation of mRNAs encoding mitochondrial-function proteins, thereby increasing mitochondrial mass and ATP production [PMID:24656129]. PRR16 also promotes epithelial–mesenchymal transition (EMT) by physically binding ABI2 and relieving its inhibition of ABL1 kinase, leading to ABL1 activation (Y412 phosphorylation) and enhanced cell migration and invasion [PMID:35719027].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"The mechanism by which mammalian cells control their size outside the canonical mTOR and Hippo pathways was unknown; a genetic screen identified PRR16 (Largen) as a cell-size regulator that preferentially stimulates translation of mitochondrial-function mRNAs, increasing mitochondrial mass and ATP production.\",\n      \"evidence\": \"Genetic screen for cell-size genes, overexpression in human cells, in vitro translation assays, conditional transgenic mouse, mitochondrial mass/ATP assays\",\n      \"pmids\": [\"24656129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The direct RNA-binding or ribosome-recruitment mechanism by which Largen selects specific mRNA subsets for translational stimulation is unresolved\",\n        \"No structural information for Largen or its translational regulatory domain exists\",\n        \"Whether Largen-dependent cell-size control operates equivalently across different tissues in vivo remains untested beyond the transgenic model\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether PRR16 had roles beyond cell-size control was unclear; PRR16 was shown to bind ABI2 and relieve its inhibition of ABL1 kinase, activating ABL1 and inducing EMT-associated migration and invasion in breast cancer cells.\",\n      \"evidence\": \"Co-immunoprecipitation, overexpression and siRNA knockdown in MCF7 cells, ABL1 Y412 phosphorylation assay, migration/invasion assays\",\n      \"pmids\": [\"35719027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The PRR16–ABI2 interaction has been demonstrated by Co-IP in a single study and lacks independent replication or structural mapping of the binding interface\",\n        \"Whether the translational and EMT-promoting functions of PRR16 are mechanistically coupled or represent independent activities is unknown\",\n        \"In vivo relevance of the PRR16–ABI2–ABL1 axis in tumour progression has not been tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis by which PRR16 selectively enhances translation of specific mRNA subsets, and whether its translational and EMT-promoting functions converge on a shared mechanism, remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No RNA-binding domain or ribosome-interaction surface has been identified in PRR16\",\n        \"No proteome-wide or ribosome-profiling study has validated the translational selectivity in an independent system\",\n        \"Relationship between mitochondrial biogenesis function and ABI2/ABL1-mediated EMT induction is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ABI2\",\n      \"ABL1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}