AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:35585049", "kind": "science-record", "revision": 3, "content_hash": "sha256:107c13faa2b0b2c34f8eff91b9639c60ef5e8a457a9c055aec16f96694852820", "created_at": "2026-11-01T18:14:29Z", "updated_at": "2026-11-01T21:27:53Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis.", "doi": "10.1038/s41419-022-04921-7", "pmid": "35585049", "authors": ["Hyunjoo Kim", "Muhah Jeong", "Do-Hyeong Na", "Shin-Hyeon Ryu", "Eun Il Jeong", "Kwangmin Jung", "Jaemin Kang", "Ho-June Lee", "Taebo Sim", "Dae-Yeul Yu", "Hee Chul Yu", "Baik-Hwan Cho", "Yong-Keun Jung"], "journal": "Cell death & disease", "year": 2022, "abstract": "The RAS-BRAF signaling is a major pathway of cell proliferation and their mutations are frequently found in human cancers. Adenylate kinase 2 (AK2), which modulates balance of adenine nucleotide pool, has been implicated in cell death and cell proliferation independently of its enzyme activity. Recently, the role of AK2 in tumorigenesis was in part elucidated in some cancer types including lung adenocarcinoma and breast cancer, but the underlying mechanism is not clear. Here, we show that AK2 is a BRAF-suppressor. In in vitro assays and cell model, AK2 interacted with BRAF and inhibited BRAF activity and downstream ERK phosphorylation. Energy-deprived conditions in cell model and the addition of AMP to cell lysates strengthened the AK2-BRAF interaction, suggesting that AK2 is involved in the regulation of BRAF activity in response to cell metabolic state. AMP facilitated the AK2-BRAF complex formation through binding to AK2. In a panel of HCC cell lines, AK2 expression was inversely correlated with ERK/MAPK activation, and AK2-knockdown or -knockout increased BRAF activity and promoted cell proliferation. Tumors from HCC patients showed low-AK2 protein expression and increased ERK activation compared to non-tumor tissues and the downregulation of AK2 was also verified by two microarray datasets (TCGA-LIHC and GSE14520). Moreover, AK2/BRAF interaction was abrogated by RAS activation in in vitro assay and cell model and in a mouse model of HRASG12V-driven HCC, and AK2 ablation promoted tumor growth and BRAF activity. AK2 also bound to BRAF inhibitor-insensitive BRAF mutants and attenuated their activities. These findings indicate that AK2 monitoring cellular AMP levels is indeed a negative regulator of BRAF, linking the metabolic status to tumor growth.", "claims": [{"id": "claim-method", "statement": "Statistical analysis was performed by paired Student’s t-test.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35585049", "locator": "sections[9] \"AK2 deficiency amplifies the BRAF signal and is detected in cancer cells and tissues\" paragraph 6", "quote": "Statistical analysis was performed by paired Student’s t-test."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The Cancer Genome Atlas (TCGA) HCC microarray dataset and clinical information were obtained from ‘Firehose’ (gdac.broadinstitute.org). GSE14520 (based on the GPL3921 platform) HCC- and normal tissue- datasets and clinical information were downloaded from ‘NCBI Gene Expression Omnibus’ (www.ncbi.nlm.nih.gov/geo).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35585049", "locator": "sections[19] \"Data availability\" paragraph 2", "quote": "The Cancer Genome Atlas (TCGA) HCC microarray dataset and clinical information were obtained from ‘Firehose’ (gdac.broadinstitute.org). GSE14520 (based on the GPL3921 platform) HCC- and normal tissue- datasets and clinical information were downloaded from ‘NCBI Gene Expression Omnibus’ (www.ncbi.nlm.nih.gov/geo)."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Here, we show that AK2 is a BRAF-suppressor.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:35585049", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Here, we show that AK2 is a BRAF-suppressor."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "Here, we show that AK2 is a BRAF-suppressor.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:35585049"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": [], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": [], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:obtain_source_data blocked on data:accession_absent"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:35585049", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1038/s41419-022-04921-7", "sha256": "sha256:6c3a94532c6b8a29b00e9eabb4a029b5adf590546ab843c0280a58f487448c12", "bytes": 52018, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1038/s41419-022-04921-7", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC9117275", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}], "gaps": []}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": null, "specific": null, "label": "paired Student’s t-test", "dsl_operations": [], "missing_operations": [], "expressible": null, "parameters": {}, "data_shapes": [], "evidence": {"score": 1.0, "band": "verbatim", "quote": "Statistical analysis was performed by paired Student’s t-test."}}], "targets": [], "gaps": ["method.reader_named_unmapped"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "blocked", "tier": "R4", "blocking_axis": "data", "blocked_on": "data:accession_absent", "axes": {"method": {"tier": "R4", "expressible": false, "required_operations": [], "missing_operations": [], "basis": "The reader quoted the method the paper names (paired Student’s t-test), but the corpus's method extractor could not map it onto a DSL operation, so the method is published but not expressible."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R4", "reachable": false, "accessions": ["GSE14520-GPL3921"], "resolved_accessions": [], "statements": ["The Cancer Genome Atlas (TCGA) HCC microarray dataset and clinical information were obtained from ‘Firehose’ (gdac.broadinstitute.org). GSE14520 (based on the GPL3921 platform) HCC- and normal tissue- datasets and clinical information were downloaded from ‘NCBI Gene Expression Omnibus’ (www.ncbi.nlm.nih.gov/geo)."], "basis": "The paper names GSE14520-GPL3921, but the accession does not resolve in the repository (no reason recorded), so the data cannot be reached from here. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": [], "assets": ["source:pmid:35585049"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:None"]}, "gaps": ["data:accession_absent"]}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T17:46:35Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 16345, "completion_tokens": 1748, "cached_tokens": 188}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:35585049", "type": "paper", "label": "pmid:35585049"}, {"id": "source:pmid:35585049", "type": "manuscript", "label": "PMID 35585049 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:35585049", "type": "paper", "label": "pmid:35585049"}, {"id": "source:pmid:35585049", "type": "manuscript", "label": "PMID 35585049 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-35585049", "type": "extraction", "used": ["source:pmid:35585049"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-None", "type": "accession_resolution", "used": ["data:geo:None"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:35585049", "parent_hash": "sha256:5fc0508c5fec315b117a503b238b4810424104568361bf14a129037c0e9dc870", "fork_of": null, "generation": 2}, "gaps": ["execution.not_run", "method.reader_named_unmapped", "review.human_critique", "review.independent_reader", "review.machine_critique", "step:obtain_source_data blocked on data:accession_absent"], "assays": [{"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.85, "evidence": ["correlated with ERK/MAPK activation, and AK2-knockdown or -knockout increased BRAF activity and pro"], "order_basis": "paper_text_order:1065", "id": "assay:1"}, {"role": "data_generation", "definition_id": "microarray", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["wnregulation of AK2 was also verified by two microarray datasets (TCGA-LIHC and GSE14520). Moreover,"], "order_basis": "paper_text_order:1318", "id": "assay:2"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["on in in vitro assay and cell model and in a mouse model of HRASG12V-driven HCC, and AK2 ablation pro", "on in in vitro assay and cell model and in a mouse model of HRASG12V-driven HCC, and AK2 ablati", "Materials and methods Animal studies All mice were approved by and handled in accordance with t", ", 38] to induce liver cancer. HRAS-Tg;AK2-KO mice were generated by mating AK2+/− knockout mice [19"], "order_basis": "paper_text_order:1469", "id": "assay:3"}]}