{"gene":"WDCP","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2014,"finding":"WDCP (C2orf44) contains a C-terminal proline-rich segment that mediates binding to the Src homology 3 (SH3) domain of the Src family kinase Hck, and co-expression with Hck leads to tyrosine phosphorylation of WDCP.","method":"Protein cloning, co-expression, SH3 domain binding assay, tyrosine phosphorylation assay","journal":"Biomedical reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct binding and phosphorylation assays in a single lab with two orthogonal methods (SH3 pulldown + phosphorylation detection), but no structural validation or independent replication","pmids":["25469238"],"is_preprint":false},{"year":2014,"finding":"WDCP exists as an oligomer in mammalian cells, as determined by chromatographic fractionation of WDCP-containing lysates.","method":"Chromatographic fractionation of cell lysates","journal":"Biomedical reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single biochemical method, no structural validation","pmids":["25469238"],"is_preprint":false},{"year":2018,"finding":"WDCP (MMAP) directly interacts with MRE11 and is required for optimal stability of the MRN (MRE11-RAD50-NBS1) complex during mitosis, forming a mitosis-specific complex called mMRN. WDCP colocalizes with MRN at mitotic spindles, and WDCP-deficient cells display abnormal spindle dynamics and chromosome segregation. Both WDCP and MRE11 are hyperphosphorylated by the mitotic kinase PLK1, and this phosphorylation is required for assembly of the mMRN complex. The assembled mMRN complex enables PLK1 to interact with and activate the microtubule depolymerase KIF2A, leading to spindle turnover and chromosome segregation.","method":"Co-immunoprecipitation, colocalization imaging, siRNA knockdown with spindle/chromosome segregation phenotypic readout, phosphorylation assays, epistasis analysis of PLK1-KIF2A pathway","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, colocalization, KD with defined cellular phenotype, phosphorylation assays, and pathway placement (PLK1→mMRN→KIF2A) established by multiple orthogonal methods in a single study","pmids":["30297404"],"is_preprint":false},{"year":2012,"finding":"WDCP (C2orf44) is identified as a fusion partner of ALK in colorectal cancer, forming a C2orf44-ALK gene fusion that functions as an oncogenic driver.","method":"Next-generation sequencing of tumor specimens (cancer genomic profiling)","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NGS-based fusion identification in tumor biopsy, replicated in subsequent clinical cohort studies; direct oncogenic mechanism inferred from fusion architecture but not reconstituted in vitro in this paper","pmids":["22327622"],"is_preprint":false}],"current_model":"WDCP is a WD repeat and coiled-coil containing protein that forms a mitosis-specific complex (mMRN) with MRE11-RAD50-NBS1 following PLK1-mediated phosphorylation, which is required for spindle dynamics and chromosome segregation via PLK1-KIF2A activation; it also contains a proline-rich region that binds the SH3 domain of Hck and is tyrosine-phosphorylated by Hck, and in colorectal cancer it serves as a fusion partner for ALK, imposing an oligomeric structure that drives constitutive ALK kinase activation."},"narrative":{"mechanistic_narrative":"WDCP (C2orf44/MMAP) is a WD-repeat and coiled-coil oligomeric protein that functions as a mitotic scaffold coordinating the MRN complex with spindle dynamics [PMID:25469238, PMID:30297404]. During mitosis it directly binds MRE11 and is required for optimal stability of the MRE11-RAD50-NBS1 complex, assembling a mitosis-specific complex (mMRN) that localizes to spindles; both WDCP and MRE11 are hyperphosphorylated by PLK1, and this modification is required for mMRN assembly, which in turn enables PLK1 to engage and activate the microtubule depolymerase KIF2A to drive spindle turnover and faithful chromosome segregation [PMID:30297404]. WDCP also carries a C-terminal proline-rich segment that binds the SH3 domain of the Src-family kinase Hck and is tyrosine-phosphorylated upon Hck co-expression [PMID:25469238]. Its self-association into oligomers underlies its oncogenic role: in colorectal cancer WDCP is recurrently fused to ALK, where the imposed oligomeric architecture drives constitutive ALK kinase activation as an oncogenic driver [PMID:25469238, PMID:22327622].","teleology":[{"year":2012,"claim":"Established WDCP as a clinically relevant oncogenic locus by identifying it as a recurrent ALK fusion partner in colorectal cancer, raising the question of how a poorly characterized ORF could drive kinase activation.","evidence":"Next-generation sequencing of colorectal tumor specimens","pmids":["22327622"],"confidence":"Medium","gaps":["Oncogenic mechanism inferred from fusion architecture but not reconstituted in vitro","Native function of WDCP not addressed","Frequency and clinical impact across cohorts not defined here"]},{"year":2014,"claim":"Began defining WDCP's biochemical properties by showing it binds the Hck SH3 domain via a proline-rich segment and is tyrosine-phosphorylated by Hck, placing it in a Src-family kinase interaction context.","evidence":"Cloning, co-expression, SH3 pulldown and tyrosine phosphorylation assays in a single lab","pmids":["25469238"],"confidence":"Medium","gaps":["No structural validation of the SH3 interaction","Functional consequence of Hck phosphorylation unknown","Not independently replicated"]},{"year":2014,"claim":"Demonstrated that WDCP self-associates into oligomers, providing the structural basis later invoked to explain constitutive ALK activation in the fusion.","evidence":"Chromatographic fractionation of cell lysates","pmids":["25469238"],"confidence":"Low","gaps":["Single biochemical method without structural validation","Oligomerization domain and stoichiometry not defined","Link to ALK fusion activation not directly tested"]},{"year":2018,"claim":"Defined WDCP's endogenous function as a mitotic scaffold that stabilizes the MRN complex (mMRN) and couples PLK1 phosphorylation to KIF2A-dependent spindle dynamics and chromosome segregation.","evidence":"Reciprocal Co-IP, colocalization imaging, siRNA knockdown with spindle/segregation phenotypes, phosphorylation assays, and PLK1-KIF2A epistasis in a single study","pmids":["30297404"],"confidence":"High","gaps":["PLK1 phosphosites on WDCP not mapped","Structural basis of MRE11 binding not resolved","Relationship between mitotic scaffold function and ALK-fusion oncogenesis not connected"]},{"year":null,"claim":"How WDCP's oligomerization, Hck/SH3 binding, and mitotic mMRN scaffolding functions integrate—and whether any relate mechanistically to its oncogenic ALK-fusion role—remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of WDCP or its domains","Physiological role of Hck-mediated tyrosine phosphorylation unknown","Whether normal WDCP function is co-opted in the ALK fusion is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]}],"complexes":["mMRN (mitotic MRE11-RAD50-NBS1)"],"partners":["MRE11","PLK1","KIF2A","HCK","ALK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H6R7","full_name":"WD repeat and coiled-coil-containing protein","aliases":[],"length_aa":721,"mass_kda":79.1,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9H6R7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDCP","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ANKRD40","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDCP","total_profiled":1310},"omim":[{"mim_id":"616234","title":"WD REPEAT- AND COILED-COIL-CONTAINING PROTEIN; WDCP","url":"https://www.omim.org/entry/616234"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDCP"},"hgnc":{"alias_symbol":["FLJ21945","MMAP"],"prev_symbol":["C2orf44"]},"alphafold":{"accession":"Q9H6R7","domains":[{"cath_id":"2.130.10.10","chopping":"3-227_313-431","consensus_level":"medium","plddt":86.1753,"start":3,"end":431},{"cath_id":"3.10.20","chopping":"601-675","consensus_level":"high","plddt":88.088,"start":601,"end":675}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6R7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6R7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6R7-F1-predicted_aligned_error_v6.png","plddt_mean":67.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDCP","jax_strain_url":"https://www.jax.org/strain/search?query=WDCP"},"sequence":{"accession":"Q9H6R7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H6R7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H6R7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6R7"}},"corpus_meta":[{"pmid":"22327622","id":"PMC_22327622","title":"Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies.","date":"2012","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22327622","citation_count":711,"is_preprint":false},{"pmid":"11076973","id":"PMC_11076973","title":"Lava lamp, a novel peripheral golgi protein, is required for Drosophila melanogaster cellularization.","date":"2000","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11076973","citation_count":248,"is_preprint":false},{"pmid":"26933125","id":"PMC_26933125","title":"Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/26933125","citation_count":99,"is_preprint":false},{"pmid":"26067391","id":"PMC_26067391","title":"Differential DNA methylation identified in the blood and retina of AMD patients.","date":"2015","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26067391","citation_count":63,"is_preprint":false},{"pmid":"12392792","id":"PMC_12392792","title":"Effects of chronic intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) in aged Rhesus monkeys.","date":"2002","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/12392792","citation_count":60,"is_preprint":false},{"pmid":"30297404","id":"PMC_30297404","title":"Mitosis-specific MRN complex promotes a mitotic signaling cascade to regulate spindle dynamics and chromosome segregation.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30297404","citation_count":24,"is_preprint":false},{"pmid":"36511548","id":"PMC_36511548","title":"Computing committors via Mahalanobis diffusion maps with enhanced sampling data.","date":"2022","source":"The Journal of chemical physics","url":"https://pubmed.ncbi.nlm.nih.gov/36511548","citation_count":14,"is_preprint":false},{"pmid":"32221272","id":"PMC_32221272","title":"Injury and Apoptosis in the Palatopharyngeal Muscle in Patients with Obstructive Sleep Apnea-Hypopnea Syndrome.","date":"2020","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/32221272","citation_count":9,"is_preprint":false},{"pmid":"34517547","id":"PMC_34517547","title":"Analysis of the role of METTL5 as a hub gene in lung adenocarcinoma based on a weighted gene co-expression network.","date":"2021","source":"Mathematical biosciences and engineering : MBE","url":"https://pubmed.ncbi.nlm.nih.gov/34517547","citation_count":8,"is_preprint":false},{"pmid":"30482799","id":"PMC_30482799","title":"OCMA: Fast, Memory-Efficient Factorization of Prohibitively Large Relationship Matrices.","date":"2019","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/30482799","citation_count":4,"is_preprint":false},{"pmid":"25469238","id":"PMC_25469238","title":"Molecular characterization of WDCP, a novel fusion partner for the anaplastic lymphoma tyrosine kinase ALK.","date":"2014","source":"Biomedical reports","url":"https://pubmed.ncbi.nlm.nih.gov/25469238","citation_count":3,"is_preprint":false},{"pmid":"23584553","id":"PMC_23584553","title":"Assessment of the photosensitization properties of cationic porphyrins in interaction with DNA nucleotide pairs.","date":"2013","source":"Journal of molecular modeling","url":"https://pubmed.ncbi.nlm.nih.gov/23584553","citation_count":1,"is_preprint":false},{"pmid":"41564481","id":"PMC_41564481","title":"A microfluidic microspheres accumulation platform for direct visualization of urine albumin-to-creatinine ratio in patients with chronic kidney disease.","date":"2026","source":"Biosensors & bioelectronics","url":"https://pubmed.ncbi.nlm.nih.gov/41564481","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8242,"output_tokens":1123,"usd":0.020785,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7656,"output_tokens":1807,"usd":0.041728,"stage2_stop_reason":"end_turn"},"total_usd":0.062513,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"WDCP (C2orf44) contains a C-terminal proline-rich segment that mediates binding to the Src homology 3 (SH3) domain of the Src family kinase Hck, and co-expression with Hck leads to tyrosine phosphorylation of WDCP.\",\n      \"method\": \"Protein cloning, co-expression, SH3 domain binding assay, tyrosine phosphorylation assay\",\n      \"journal\": \"Biomedical reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct binding and phosphorylation assays in a single lab with two orthogonal methods (SH3 pulldown + phosphorylation detection), but no structural validation or independent replication\",\n      \"pmids\": [\"25469238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"WDCP exists as an oligomer in mammalian cells, as determined by chromatographic fractionation of WDCP-containing lysates.\",\n      \"method\": \"Chromatographic fractionation of cell lysates\",\n      \"journal\": \"Biomedical reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single biochemical method, no structural validation\",\n      \"pmids\": [\"25469238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WDCP (MMAP) directly interacts with MRE11 and is required for optimal stability of the MRN (MRE11-RAD50-NBS1) complex during mitosis, forming a mitosis-specific complex called mMRN. WDCP colocalizes with MRN at mitotic spindles, and WDCP-deficient cells display abnormal spindle dynamics and chromosome segregation. Both WDCP and MRE11 are hyperphosphorylated by the mitotic kinase PLK1, and this phosphorylation is required for assembly of the mMRN complex. The assembled mMRN complex enables PLK1 to interact with and activate the microtubule depolymerase KIF2A, leading to spindle turnover and chromosome segregation.\",\n      \"method\": \"Co-immunoprecipitation, colocalization imaging, siRNA knockdown with spindle/chromosome segregation phenotypic readout, phosphorylation assays, epistasis analysis of PLK1-KIF2A pathway\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, colocalization, KD with defined cellular phenotype, phosphorylation assays, and pathway placement (PLK1→mMRN→KIF2A) established by multiple orthogonal methods in a single study\",\n      \"pmids\": [\"30297404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"WDCP (C2orf44) is identified as a fusion partner of ALK in colorectal cancer, forming a C2orf44-ALK gene fusion that functions as an oncogenic driver.\",\n      \"method\": \"Next-generation sequencing of tumor specimens (cancer genomic profiling)\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NGS-based fusion identification in tumor biopsy, replicated in subsequent clinical cohort studies; direct oncogenic mechanism inferred from fusion architecture but not reconstituted in vitro in this paper\",\n      \"pmids\": [\"22327622\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDCP is a WD repeat and coiled-coil containing protein that forms a mitosis-specific complex (mMRN) with MRE11-RAD50-NBS1 following PLK1-mediated phosphorylation, which is required for spindle dynamics and chromosome segregation via PLK1-KIF2A activation; it also contains a proline-rich region that binds the SH3 domain of Hck and is tyrosine-phosphorylated by Hck, and in colorectal cancer it serves as a fusion partner for ALK, imposing an oligomeric structure that drives constitutive ALK kinase activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDCP (C2orf44/MMAP) is a WD-repeat and coiled-coil oligomeric protein that functions as a mitotic scaffold coordinating the MRN complex with spindle dynamics [#1, #2]. During mitosis it directly binds MRE11 and is required for optimal stability of the MRE11-RAD50-NBS1 complex, assembling a mitosis-specific complex (mMRN) that localizes to spindles; both WDCP and MRE11 are hyperphosphorylated by PLK1, and this modification is required for mMRN assembly, which in turn enables PLK1 to engage and activate the microtubule depolymerase KIF2A to drive spindle turnover and faithful chromosome segregation [#2]. WDCP also carries a C-terminal proline-rich segment that binds the SH3 domain of the Src-family kinase Hck and is tyrosine-phosphorylated upon Hck co-expression [#0]. Its self-association into oligomers underlies its oncogenic role: in colorectal cancer WDCP is recurrently fused to ALK, where the imposed oligomeric architecture drives constitutive ALK kinase activation as an oncogenic driver [#1, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established WDCP as a clinically relevant oncogenic locus by identifying it as a recurrent ALK fusion partner in colorectal cancer, raising the question of how a poorly characterized ORF could drive kinase activation.\",\n      \"evidence\": \"Next-generation sequencing of colorectal tumor specimens\",\n      \"pmids\": [\"22327622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oncogenic mechanism inferred from fusion architecture but not reconstituted in vitro\", \"Native function of WDCP not addressed\", \"Frequency and clinical impact across cohorts not defined here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Began defining WDCP's biochemical properties by showing it binds the Hck SH3 domain via a proline-rich segment and is tyrosine-phosphorylated by Hck, placing it in a Src-family kinase interaction context.\",\n      \"evidence\": \"Cloning, co-expression, SH3 pulldown and tyrosine phosphorylation assays in a single lab\",\n      \"pmids\": [\"25469238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural validation of the SH3 interaction\", \"Functional consequence of Hck phosphorylation unknown\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that WDCP self-associates into oligomers, providing the structural basis later invoked to explain constitutive ALK activation in the fusion.\",\n      \"evidence\": \"Chromatographic fractionation of cell lysates\",\n      \"pmids\": [\"25469238\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single biochemical method without structural validation\", \"Oligomerization domain and stoichiometry not defined\", \"Link to ALK fusion activation not directly tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined WDCP's endogenous function as a mitotic scaffold that stabilizes the MRN complex (mMRN) and couples PLK1 phosphorylation to KIF2A-dependent spindle dynamics and chromosome segregation.\",\n      \"evidence\": \"Reciprocal Co-IP, colocalization imaging, siRNA knockdown with spindle/segregation phenotypes, phosphorylation assays, and PLK1-KIF2A epistasis in a single study\",\n      \"pmids\": [\"30297404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PLK1 phosphosites on WDCP not mapped\", \"Structural basis of MRE11 binding not resolved\", \"Relationship between mitotic scaffold function and ALK-fusion oncogenesis not connected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDCP's oligomerization, Hck/SH3 binding, and mitotic mMRN scaffolding functions integrate—and whether any relate mechanistically to its oncogenic ALK-fusion role—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of WDCP or its domains\", \"Physiological role of Hck-mediated tyrosine phosphorylation unknown\", \"Whether normal WDCP function is co-opted in the ALK fusion is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"mMRN (mitotic MRE11-RAD50-NBS1)\"],\n    \"partners\": [\"MRE11\", \"PLK1\", \"KIF2A\", \"HCK\", \"ALK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}