{"gene":"ARL14","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2020,"finding":"The N-terminal amphipathic helix of Arl14 is sufficient to determine its subcellular localization to endosomes and the plasma membrane, independent of GTP binding. Exchanging the amphipathic helix of Arl14 with that of Golgi-localized Arfrp1 switches Arl14's localization to the Golgi, and vice versa. The amphipathic helix alone is sufficient to redirect cytosolic proteins to the specific compartment. Myristoylation of the Arl14 amphipathic helix is required for this specific subcellular localization. Notably, Arl14 is recruited to its membrane compartment independently of GTP binding, indicating that membrane association and activation are uncoupled for this protein.","method":"Chimeric Arf protein swaps (exchanging amphipathic helices between Arfrp1 and Arl14), subcellular localization imaging, mutagenesis of myristoylation and acetylation residues, GTP-binding mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain-swap mutagenesis combined with localization imaging and GTP-binding mutants in a single study with multiple orthogonal approaches","pmids":["32972971"],"is_preprint":false},{"year":2019,"finding":"Silencing of ARL14 in lung adenocarcinoma cells inhibits cell proliferation, migration, and invasion, blocks the ERK/p38 MAPK signaling pathway, induces G0 cell cycle arrest leading to cell dormancy, and enhances expression of CIDEC (a cell death activator with opposing roles in proliferation/migration). ARL14 knockdown had no effect on normal lung cell proliferation, indicating tumor-specific dependency.","method":"siRNA knockdown of ARL14 in lung adenocarcinoma cells; readouts: proliferation assays, migration/invasion assays, cell cycle analysis (flow cytometry), western blot for ERK/p38 pathway and CIDEC expression","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — single lab, single gene KD with multiple cellular phenotype readouts but no pathway rescue or orthogonal mechanistic validation","pmids":["31750299"],"is_preprint":false}],"current_model":"Human ARL14 (ARF7) is an endosome- and plasma membrane-localized Arf-family small GTPase whose subcellular targeting is determined by its N-terminal amphipathic helix in a GTP-independent, myristoylation-dependent manner; in lung adenocarcinoma cells, ARL14 supports proliferation, migration, and invasion through activation of the ERK/p38 MAPK signaling pathway and suppression of CIDEC."},"narrative":{"mechanistic_narrative":"ARL14 (ARF7) is an Arf-family small GTPase that localizes to endosomes and the plasma membrane, where its targeting is dictated by an N-terminal amphipathic helix in a myristoylation-dependent but GTP-independent manner; swapping this helix with that of the Golgi-localized Arfrp1 redirects ARL14 to the Golgi, and the helix alone suffices to relocate cytosolic proteins, demonstrating that membrane association and GTP-dependent activation are uncoupled for this protein [PMID:32972971]. In lung adenocarcinoma cells, ARL14 supports proliferation, migration, and invasion, and its silencing blocks ERK/p38 MAPK signaling, drives G0 cell cycle arrest, and de-represses CIDEC, with no effect on normal lung cells, indicating a tumor-specific dependency [PMID:31750299]. Beyond these findings, no further mechanistic detail—including direct effectors, GEFs/GAPs, or the structural basis of its signaling output—has been characterized in the available corpus.","teleology":[{"year":2019,"claim":"Whether ARL14 contributes to tumor cell behavior was unknown; knockdown established it as a tumor-specific driver of proliferation, migration, and invasion acting upstream of ERK/p38 MAPK and CIDEC.","evidence":"siRNA knockdown in lung adenocarcinoma cells with proliferation, migration/invasion, flow-cytometry cell cycle, and western blot readouts","pmids":["31750299"],"confidence":"Medium","gaps":["no pathway rescue to confirm ERK/p38 and CIDEC are direct downstream effectors","direct molecular link between ARL14 GTPase activity and MAPK activation not established","single-system result not extended beyond lung adenocarcinoma"]},{"year":2020,"claim":"How ARL14 achieves its membrane targeting was unresolved; domain-swap and mutagenesis experiments showed the N-terminal amphipathic helix is necessary and sufficient for endosome/plasma membrane localization via myristoylation, and that this occurs independently of GTP binding.","evidence":"chimeric amphipathic-helix swaps between Arfrp1 and Arl14, localization imaging, myristoylation/acetylation and GTP-binding mutants","pmids":["32972971"],"confidence":"High","gaps":["the GTP-bound effectors and GEF/GAP regulators of ARL14 remain unidentified","functional consequence of localization for downstream signaling not connected to the MAPK/CIDEC role","no structural model of the helix-membrane interaction"]},{"year":null,"claim":"It remains unknown what direct effectors couple membrane-anchored ARL14 to ERK/p38 MAPK activation and CIDEC suppression, and what regulates its GTPase cycle.","evidence":"","pmids":[],"confidence":"Low","gaps":["no GEF, GAP, or direct effector identified","mechanistic bridge between localization and signaling output unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N4G2","full_name":"ADP-ribosylation factor-like protein 14","aliases":["ADP-ribosylation factor 7"],"length_aa":192,"mass_kda":21.6,"function":"GTPase that recruits MYO1E to MHC class II-containing vesicles via the effector protein ARL14EP and hence controls the movement of these vesicles along the actin cytoskeleton in dendritic cells","subcellular_location":"Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/Q8N4G2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARL14","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/ARL14","total_profiled":1310},"omim":[{"mim_id":"614442","title":"PLECKSTRIN AND SEC7 DOMAINS-CONTAINING PROTEIN 4; PSD4","url":"https://www.omim.org/entry/614442"},{"mim_id":"614439","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 14; ARL14","url":"https://www.omim.org/entry/614439"},{"mim_id":"612295","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 14 EFFECTOR PROTEIN; ARL14EP","url":"https://www.omim.org/entry/612295"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"gallbladder","ntpm":120.8},{"tissue":"intestine","ntpm":48.2},{"tissue":"stomach 1","ntpm":72.9}],"url":"https://www.proteinatlas.org/search/ARL14"},"hgnc":{"alias_symbol":["FLJ22595"],"prev_symbol":["ARF7"]},"alphafold":{"accession":"Q8N4G2","domains":[{"cath_id":"3.40.50.300","chopping":"13-185","consensus_level":"high","plddt":96.5617,"start":13,"end":185}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N4G2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N4G2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N4G2-F1-predicted_aligned_error_v6.png","plddt_mean":92.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARL14","jax_strain_url":"https://www.jax.org/strain/search?query=ARL14"},"sequence":{"accession":"Q8N4G2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N4G2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N4G2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N4G2"}},"corpus_meta":[{"pmid":"15960621","id":"PMC_15960621","title":"NPH4/ARF7 and ARF19 promote leaf expansion and auxin-induced lateral root formation.","date":"2005","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15960621","citation_count":305,"is_preprint":false},{"pmid":"30573626","id":"PMC_30573626","title":"Root branching toward water involves posttranslational modification of transcription factor ARF7.","date":"2018","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30573626","citation_count":206,"is_preprint":false},{"pmid":"27217573","id":"PMC_27217573","title":"Auxin-dependent compositional change in Mediator in ARF7- and ARF19-mediated transcription.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27217573","citation_count":89,"is_preprint":false},{"pmid":"20043234","id":"PMC_20043234","title":"Involvement of auxin signaling mediated by IAA14 and ARF7/19 in membrane lipid remodeling during phosphate starvation.","date":"2009","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20043234","citation_count":62,"is_preprint":false},{"pmid":"32320660","id":"PMC_32320660","title":"The Asymmetric Expression of SAUR Genes Mediated by ARF7/19 Promotes the Gravitropism and Phototropism of Plant Hypocotyls.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32320660","citation_count":41,"is_preprint":false},{"pmid":"37224012","id":"PMC_37224012","title":"ERF1 inhibits lateral root emergence by promoting local auxin accumulation and repressing ARF7 expression.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37224012","citation_count":21,"is_preprint":false},{"pmid":"31750299","id":"PMC_31750299","title":"Silencing of ARL14 Gene Induces Lung Adenocarcinoma Cells to a Dormant State.","date":"2019","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/31750299","citation_count":20,"is_preprint":false},{"pmid":"38684906","id":"PMC_38684906","title":"NBR1-mediated selective autophagy of ARF7 modulates root branching.","date":"2024","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/38684906","citation_count":13,"is_preprint":false},{"pmid":"32972971","id":"PMC_32972971","title":"The amphipathic helices of Arfrp1 and Arl14 are sufficient to determine subcellular localizations.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32972971","citation_count":13,"is_preprint":false},{"pmid":"39722601","id":"PMC_39722601","title":"Sinomonas gamaensis NEAU-HV1 remodels the IAA14-ARF7/19 interaction to promote plant growth.","date":"2024","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/39722601","citation_count":12,"is_preprint":false},{"pmid":"40571787","id":"PMC_40571787","title":"BZR1 promotes pluripotency acquisition and callus development through direct regulation of ARF7 and ARF19.","date":"2025","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/40571787","citation_count":5,"is_preprint":false},{"pmid":"38531688","id":"PMC_38531688","title":"From Genome-wide Association Studies to Functional Variants: ARL14 Cis-regulatory Variants Are Associated With Severe Malaria.","date":"2024","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38531688","citation_count":4,"is_preprint":false},{"pmid":"37354348","id":"PMC_37354348","title":"LBD18 and IAA14 antagonistically interact with ARF7 via the invariant Lys and acidic residues of the OPCA motif in the PB1 domain.","date":"2023","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/37354348","citation_count":3,"is_preprint":false},{"pmid":"38832021","id":"PMC_38832021","title":"The first intron of ARF7 is required for expression in root tips.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38832021","citation_count":0,"is_preprint":false},{"pmid":"40409727","id":"PMC_40409727","title":"Auxin promotes stem secondary growth of Poncirus trifoliata seedling through ARF7 modulating xylem development.","date":"2025","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/40409727","citation_count":0,"is_preprint":false},{"pmid":"40988476","id":"PMC_40988476","title":"ARF7/19 activate CRF3 in response to cold via Aux/IAA degradation.","date":"2025","source":"Journal of integrative plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/40988476","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.15.648910","title":"<i>SlHSFB3a</i>  developmentally regulates lateral root formation by modulating auxin signaling in tomato","date":"2025-04-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.15.648910","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.30.662278","title":"Pathogenic fungus exploits the lateral root regulators to induce pluripotency in maize shoots","date":"2025-07-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.30.662278","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9899,"output_tokens":1135,"usd":0.023361,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7185,"output_tokens":1435,"usd":0.0359,"stage2_stop_reason":"end_turn"},"total_usd":0.059261,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to classify each paper:\n\n- Papers 1-6, 8-11, 13-18: These describe ARF7 which is the **Arabidopsis** auxin response factor (NPH4/ARF7), an Arabidopsis transcription factor. The human gene ARL14 (also known as ARF7) is an ADP-ribosylation factor-like GTPase, a completely different protein. These are symbol collisions — the plant ARF7 is unrelated to human ARL14.\n\n- Paper 7: \"Silencing of ARL14 Gene Induces Lung Adenocarcinoma Cells to a Dormant State\" — This is about human ARL14 in lung cancer cells. INCLUDE.\n\n- Paper 9: \"The amphipathic helices of Arfrp1 and Arl14 are sufficient to determine subcellular localizations\" — This describes Arl14 as an \"endosome- and plasma membrane-localized Arf family protein.\" This is about the mammalian ARL14 GTPase. INCLUDE.\n\n- Paper 12: \"ARL14 Cis-regulatory Variants Are Associated With Severe Malaria\" — This is about human ARL14 and immune cells, but the mechanism is regulatory/GWAS-based, not protein mechanism. The gene reporter assay shows promoter activity of the ARL14 locus. This is expression-level, not protein mechanism. EXCLUDE.\n\nSo only papers 7 and 9 are about human ARL14.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"The N-terminal amphipathic helix of Arl14 is sufficient to determine its subcellular localization to endosomes and the plasma membrane, independent of GTP binding. Exchanging the amphipathic helix of Arl14 with that of Golgi-localized Arfrp1 switches Arl14's localization to the Golgi, and vice versa. The amphipathic helix alone is sufficient to redirect cytosolic proteins to the specific compartment. Myristoylation of the Arl14 amphipathic helix is required for this specific subcellular localization. Notably, Arl14 is recruited to its membrane compartment independently of GTP binding, indicating that membrane association and activation are uncoupled for this protein.\",\n      \"method\": \"Chimeric Arf protein swaps (exchanging amphipathic helices between Arfrp1 and Arl14), subcellular localization imaging, mutagenesis of myristoylation and acetylation residues, GTP-binding mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain-swap mutagenesis combined with localization imaging and GTP-binding mutants in a single study with multiple orthogonal approaches\",\n      \"pmids\": [\"32972971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Silencing of ARL14 in lung adenocarcinoma cells inhibits cell proliferation, migration, and invasion, blocks the ERK/p38 MAPK signaling pathway, induces G0 cell cycle arrest leading to cell dormancy, and enhances expression of CIDEC (a cell death activator with opposing roles in proliferation/migration). ARL14 knockdown had no effect on normal lung cell proliferation, indicating tumor-specific dependency.\",\n      \"method\": \"siRNA knockdown of ARL14 in lung adenocarcinoma cells; readouts: proliferation assays, migration/invasion assays, cell cycle analysis (flow cytometry), western blot for ERK/p38 pathway and CIDEC expression\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — single lab, single gene KD with multiple cellular phenotype readouts but no pathway rescue or orthogonal mechanistic validation\",\n      \"pmids\": [\"31750299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human ARL14 (ARF7) is an endosome- and plasma membrane-localized Arf-family small GTPase whose subcellular targeting is determined by its N-terminal amphipathic helix in a GTP-independent, myristoylation-dependent manner; in lung adenocarcinoma cells, ARL14 supports proliferation, migration, and invasion through activation of the ERK/p38 MAPK signaling pathway and suppression of CIDEC.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARL14 (ARF7) is an Arf-family small GTPase that localizes to endosomes and the plasma membrane, where its targeting is dictated by an N-terminal amphipathic helix in a myristoylation-dependent but GTP-independent manner; swapping this helix with that of the Golgi-localized Arfrp1 redirects ARL14 to the Golgi, and the helix alone suffices to relocate cytosolic proteins, demonstrating that membrane association and GTP-dependent activation are uncoupled for this protein [#0]. In lung adenocarcinoma cells, ARL14 supports proliferation, migration, and invasion, and its silencing blocks ERK/p38 MAPK signaling, drives G0 cell cycle arrest, and de-represses CIDEC, with no effect on normal lung cells, indicating a tumor-specific dependency [#1]. Beyond these findings, no further mechanistic detail—including direct effectors, GEFs/GAPs, or the structural basis of its signaling output—has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether ARL14 contributes to tumor cell behavior was unknown; knockdown established it as a tumor-specific driver of proliferation, migration, and invasion acting upstream of ERK/p38 MAPK and CIDEC.\",\n      \"evidence\": \"siRNA knockdown in lung adenocarcinoma cells with proliferation, migration/invasion, flow-cytometry cell cycle, and western blot readouts\",\n      \"pmids\": [\"31750299\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"single lab, single gene KD without rescue or orthogonal mechanistic validation\",\n      \"gaps\": [\n        \"no pathway rescue to confirm ERK/p38 and CIDEC are direct downstream effectors\",\n        \"direct molecular link between ARL14 GTPase activity and MAPK activation not established\",\n        \"single-system result not extended beyond lung adenocarcinoma\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"How ARL14 achieves its membrane targeting was unresolved; domain-swap and mutagenesis experiments showed the N-terminal amphipathic helix is necessary and sufficient for endosome/plasma membrane localization via myristoylation, and that this occurs independently of GTP binding.\",\n      \"evidence\": \"chimeric amphipathic-helix swaps between Arfrp1 and Arl14, localization imaging, myristoylation/acetylation and GTP-binding mutants\",\n      \"pmids\": [\"32972971\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"multiple orthogonal approaches in one study\",\n      \"gaps\": [\n        \"the GTP-bound effectors and GEF/GAP regulators of ARL14 remain unidentified\",\n        \"functional consequence of localization for downstream signaling not connected to the MAPK/CIDEC role\",\n        \"no structural model of the helix-membrane interaction\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what direct effectors couple membrane-anchored ARL14 to ERK/p38 MAPK activation and CIDEC suppression, and what regulates its GTPase cycle.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"no GEF, GAP, or direct effector identified\",\n        \"mechanistic bridge between localization and signaling output unestablished\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}