{"gene":"PDIK1L","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2003,"finding":"PDIK1L encodes a 341 amino acid protein with kinase domain showing 69% identity to CLIK1 (CLP-36 interacting kinase); bioinformatics analysis suggests interaction with PDZ and LIM domain proteins; the protein localizes to the nucleus.","method":"cDNA cloning from human foetal brain library, bioinformatics analysis, subcellular localization inference","journal":"Journal of genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/bioinformatics prediction of interaction and nuclear localization without direct experimental validation of function or binding","pmids":["14631099"],"is_preprint":false},{"year":2009,"finding":"PDIK1L (STK35L2) was identified as a close homolog of STK35L1 (STK35 long), conserved throughout vertebrates; these kinases form the NKF4 family together with STK35L3.","method":"Comparative genomics, synteny analysis, gene structure analysis, homology searches","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 / Weak — purely computational/genomic characterization, no direct functional experiments on PDIK1L itself","pmids":["19756140"],"is_preprint":false},{"year":2022,"finding":"PDIK1L forms a physical complex with the nuclear phosphatase SCP4 and acts as both a binding partner and substrate of SCP4; SCP4 activates PDIK1L through two mechanisms: catalytic removal of inhibitory phosphorylation on PDIK1L, and promotion of PDIK1L protein stability. PDIK1L functions catalytically and redundantly with its paralog STK35 in the same pathway to maintain AML proliferation and support amino acid biosynthesis and transport.","method":"Mass spectrometry of affinity-purified complexes (AP-MS), CRISPR exon scanning, gene complementation assays, domain-focused CRISPR screening","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal AP-MS identifying physical complex, genetic complementation validating catalytic function, CRISPR epistasis placing PDIK1L in same pathway as SCP4 and STK35, multiple orthogonal methods in one study","pmids":["35021089"],"is_preprint":false},{"year":2025,"finding":"PDIK1L knockdown in prostate cancer cell lines suppressed proliferation and sensitized cells to PARP inhibitors, while overexpression accelerated proliferation and conferred PARP inhibitor resistance; PDIK1L was found to interact with DNA repair and metabolic adaptation pathways.","method":"Genetic modulation (knockdown/overexpression) in prostate cancer cell lines, proliferation assays, drug sensitivity assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — clean KD/OE with defined cellular phenotype, but pathway placement is largely inferred from multi-omics without direct biochemical validation of mechanism","pmids":["41262299"],"is_preprint":false}],"current_model":"PDIK1L is a nuclear serine/threonine kinase that forms a functional complex with the nuclear phosphatase SCP4, which activates PDIK1L by removing inhibitory phosphorylation and promoting its stability; together with its paralog STK35, PDIK1L functions catalytically and redundantly in a phosphatase-kinase signaling axis that supports amino acid biosynthesis/transport and proliferation in AML cells, and its activity also modulates DNA repair and metabolic pathways in prostate cancer."},"narrative":{"mechanistic_narrative":"PDIK1L is a nuclear serine/threonine kinase that functions in a phosphatase-kinase signaling axis supporting cancer cell proliferation [PMID:35021089]. It forms a physical complex with the nuclear phosphatase SCP4, serving as both a binding partner and a substrate: SCP4 activates PDIK1L by catalytically removing inhibitory phosphorylation and by promoting PDIK1L protein stability [PMID:35021089]. Acting catalytically and redundantly with its paralog STK35 in the same pathway, PDIK1L sustains acute myeloid leukemia proliferation and supports amino acid biosynthesis and transport [PMID:35021089]. In prostate cancer cells, PDIK1L promotes proliferation and confers resistance to PARP inhibitors, linking its activity to DNA repair and metabolic adaptation pathways [PMID:41262299]. Beyond these findings, the direct kinase substrates of PDIK1L and the molecular basis of its nuclear localization have not been characterized in the available corpus.","teleology":[{"year":2003,"claim":"Initial cloning established PDIK1L as a kinase-domain protein and predicted nuclear localization, defining it as a candidate signaling enzyme before any function was known.","evidence":"cDNA cloning from human foetal brain library with bioinformatics and subcellular localization inference","pmids":["14631099"],"confidence":"Low","gaps":["Nuclear localization and PDZ/LIM-protein interaction were predicted computationally, not experimentally validated","No catalytic activity or substrate demonstrated","No cellular function assigned"]},{"year":2009,"claim":"Comparative genomics placed PDIK1L within the vertebrate-conserved NKF4 kinase family alongside STK35, framing the paralog relationship later shown to be functionally redundant.","evidence":"Comparative genomics, synteny and gene-structure analysis, homology searches","pmids":["19756140"],"confidence":"Low","gaps":["Family assignment is purely computational","No functional experiments on PDIK1L itself","Redundancy with STK35 not yet tested"]},{"year":2022,"claim":"Reciprocal complex isolation and genetic dissection answered how PDIK1L is regulated and where it acts, establishing it as an SCP4-activated kinase operating redundantly with STK35 to sustain leukemia proliferation and amino acid metabolism.","evidence":"AP-MS of affinity-purified complexes, CRISPR exon scanning, gene complementation, and domain-focused CRISPR screening in AML cells","pmids":["35021089"],"confidence":"High","gaps":["Direct phosphorylation substrates of PDIK1L not identified","The specific inhibitory phosphosite(s) removed by SCP4 not mapped","Mechanistic link from kinase activity to amino acid biosynthesis/transport not resolved"]},{"year":2025,"claim":"Loss- and gain-of-function in prostate cancer extended PDIK1L's pro-proliferative role to a new tumor context and tied its activity to PARP-inhibitor sensitivity and DNA repair/metabolic adaptation.","evidence":"Knockdown/overexpression in prostate cancer cell lines with proliferation and drug-sensitivity assays plus multi-omics pathway inference","pmids":["41262299"],"confidence":"Medium","gaps":["Pathway placement inferred from multi-omics without direct biochemical validation","No demonstration that SCP4/STK35 axis operates in prostate cancer","Molecular mechanism connecting PDIK1L to DNA repair not established"]},{"year":null,"claim":"The direct catalytic substrates of PDIK1L and how its kinase activity mechanistically drives amino acid metabolism and DNA repair remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No phosphorylation substrate identified","No structural model of the PDIK1L-SCP4 complex","Mechanism of nuclear recruitment unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["SCP4","STK35"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N165","full_name":"Serine/threonine-protein kinase PDIK1L","aliases":["PDLIM1-interacting kinase 1-like"],"length_aa":341,"mass_kda":38.5,"function":"","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8N165/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDIK1L","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PDIK1L","total_profiled":1310},"omim":[{"mim_id":"610785","title":"PDLIM1-INTERACTING KINASE 1-LIKE; PDIK1L","url":"https://www.omim.org/entry/610785"},{"mim_id":"114500","title":"COLORECTAL CANCER; CRC","url":"https://www.omim.org/entry/114500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PDIK1L"},"hgnc":{"alias_symbol":["CLIK1L","STK35L2"],"prev_symbol":[]},"alphafold":{"accession":"Q8N165","domains":[{"cath_id":"3.30.200.20","chopping":"7-119","consensus_level":"high","plddt":90.7464,"start":7,"end":119},{"cath_id":"1.10.510.10","chopping":"124-336","consensus_level":"high","plddt":86.3836,"start":124,"end":336}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N165","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N165-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N165-F1-predicted_aligned_error_v6.png","plddt_mean":85.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDIK1L","jax_strain_url":"https://www.jax.org/strain/search?query=PDIK1L"},"sequence":{"accession":"Q8N165","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N165.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N165/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N165"}},"corpus_meta":[{"pmid":"27485360","id":"PMC_27485360","title":"Panel of Autoimmune Markers for Noninvasive Diagnosis of Minimal-Mild Endometriosis.","date":"2016","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/27485360","citation_count":29,"is_preprint":false},{"pmid":"20403595","id":"PMC_20403595","title":"Serum anti-PDIK1L autoantibody as a novel marker for endometriosis.","date":"2010","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/20403595","citation_count":19,"is_preprint":false},{"pmid":"19756140","id":"PMC_19756140","title":"Identifying and characterizing a novel protein kinase STK35L1 and deciphering its orthologs and close-homologs in vertebrates.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19756140","citation_count":10,"is_preprint":false},{"pmid":"14631099","id":"PMC_14631099","title":"Molecular cloning and characterization of a novel human kinase gene, PDIK1L.","date":"2003","source":"Journal of genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14631099","citation_count":6,"is_preprint":false},{"pmid":"35021089","id":"PMC_35021089","title":"SCP4-STK35/PDIK1L complex is a dual phospho-catalytic signaling dependency in acute myeloid leukemia.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35021089","citation_count":4,"is_preprint":false},{"pmid":"41262299","id":"PMC_41262299","title":"Metabolic subtyping reveals PDIK1L as a dual-functional regulator of progression and PARP inhibitor sensitivity in prostate cancer.","date":"2025","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/41262299","citation_count":0,"is_preprint":false},{"pmid":"39540991","id":"PMC_39540991","title":"Identification of diagnostic genes and the miRNA‒mRNA‒TF regulatory network in human oocyte aging via machine learning methods.","date":"2024","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39540991","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5944,"output_tokens":1024,"usd":0.016596,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7582,"output_tokens":1719,"usd":0.040442,"stage2_stop_reason":"end_turn"},"total_usd":0.057038,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"PDIK1L encodes a 341 amino acid protein with kinase domain showing 69% identity to CLIK1 (CLP-36 interacting kinase); bioinformatics analysis suggests interaction with PDZ and LIM domain proteins; the protein localizes to the nucleus.\",\n      \"method\": \"cDNA cloning from human foetal brain library, bioinformatics analysis, subcellular localization inference\",\n      \"journal\": \"Journal of genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/bioinformatics prediction of interaction and nuclear localization without direct experimental validation of function or binding\",\n      \"pmids\": [\"14631099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PDIK1L (STK35L2) was identified as a close homolog of STK35L1 (STK35 long), conserved throughout vertebrates; these kinases form the NKF4 family together with STK35L3.\",\n      \"method\": \"Comparative genomics, synteny analysis, gene structure analysis, homology searches\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — purely computational/genomic characterization, no direct functional experiments on PDIK1L itself\",\n      \"pmids\": [\"19756140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PDIK1L forms a physical complex with the nuclear phosphatase SCP4 and acts as both a binding partner and substrate of SCP4; SCP4 activates PDIK1L through two mechanisms: catalytic removal of inhibitory phosphorylation on PDIK1L, and promotion of PDIK1L protein stability. PDIK1L functions catalytically and redundantly with its paralog STK35 in the same pathway to maintain AML proliferation and support amino acid biosynthesis and transport.\",\n      \"method\": \"Mass spectrometry of affinity-purified complexes (AP-MS), CRISPR exon scanning, gene complementation assays, domain-focused CRISPR screening\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal AP-MS identifying physical complex, genetic complementation validating catalytic function, CRISPR epistasis placing PDIK1L in same pathway as SCP4 and STK35, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35021089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PDIK1L knockdown in prostate cancer cell lines suppressed proliferation and sensitized cells to PARP inhibitors, while overexpression accelerated proliferation and conferred PARP inhibitor resistance; PDIK1L was found to interact with DNA repair and metabolic adaptation pathways.\",\n      \"method\": \"Genetic modulation (knockdown/overexpression) in prostate cancer cell lines, proliferation assays, drug sensitivity assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — clean KD/OE with defined cellular phenotype, but pathway placement is largely inferred from multi-omics without direct biochemical validation of mechanism\",\n      \"pmids\": [\"41262299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDIK1L is a nuclear serine/threonine kinase that forms a functional complex with the nuclear phosphatase SCP4, which activates PDIK1L by removing inhibitory phosphorylation and promoting its stability; together with its paralog STK35, PDIK1L functions catalytically and redundantly in a phosphatase-kinase signaling axis that supports amino acid biosynthesis/transport and proliferation in AML cells, and its activity also modulates DNA repair and metabolic pathways in prostate cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDIK1L is a nuclear serine/threonine kinase that functions in a phosphatase-kinase signaling axis supporting cancer cell proliferation [#2]. It forms a physical complex with the nuclear phosphatase SCP4, serving as both a binding partner and a substrate: SCP4 activates PDIK1L by catalytically removing inhibitory phosphorylation and by promoting PDIK1L protein stability [#2]. Acting catalytically and redundantly with its paralog STK35 in the same pathway, PDIK1L sustains acute myeloid leukemia proliferation and supports amino acid biosynthesis and transport [#2]. In prostate cancer cells, PDIK1L promotes proliferation and confers resistance to PARP inhibitors, linking its activity to DNA repair and metabolic adaptation pathways [#3]. Beyond these findings, the direct kinase substrates of PDIK1L and the molecular basis of its nuclear localization have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Initial cloning established PDIK1L as a kinase-domain protein and predicted nuclear localization, defining it as a candidate signaling enzyme before any function was known.\",\n      \"evidence\": \"cDNA cloning from human foetal brain library with bioinformatics and subcellular localization inference\",\n      \"pmids\": [\"14631099\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Nuclear localization and PDZ/LIM-protein interaction were predicted computationally, not experimentally validated\",\n        \"No catalytic activity or substrate demonstrated\",\n        \"No cellular function assigned\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Comparative genomics placed PDIK1L within the vertebrate-conserved NKF4 kinase family alongside STK35, framing the paralog relationship later shown to be functionally redundant.\",\n      \"evidence\": \"Comparative genomics, synteny and gene-structure analysis, homology searches\",\n      \"pmids\": [\"19756140\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Family assignment is purely computational\",\n        \"No functional experiments on PDIK1L itself\",\n        \"Redundancy with STK35 not yet tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reciprocal complex isolation and genetic dissection answered how PDIK1L is regulated and where it acts, establishing it as an SCP4-activated kinase operating redundantly with STK35 to sustain leukemia proliferation and amino acid metabolism.\",\n      \"evidence\": \"AP-MS of affinity-purified complexes, CRISPR exon scanning, gene complementation, and domain-focused CRISPR screening in AML cells\",\n      \"pmids\": [\"35021089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct phosphorylation substrates of PDIK1L not identified\",\n        \"The specific inhibitory phosphosite(s) removed by SCP4 not mapped\",\n        \"Mechanistic link from kinase activity to amino acid biosynthesis/transport not resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Loss- and gain-of-function in prostate cancer extended PDIK1L's pro-proliferative role to a new tumor context and tied its activity to PARP-inhibitor sensitivity and DNA repair/metabolic adaptation.\",\n      \"evidence\": \"Knockdown/overexpression in prostate cancer cell lines with proliferation and drug-sensitivity assays plus multi-omics pathway inference\",\n      \"pmids\": [\"41262299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Pathway placement inferred from multi-omics without direct biochemical validation\",\n        \"No demonstration that SCP4/STK35 axis operates in prostate cancer\",\n        \"Molecular mechanism connecting PDIK1L to DNA repair not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct catalytic substrates of PDIK1L and how its kinase activity mechanistically drives amino acid metabolism and DNA repair remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No phosphorylation substrate identified\",\n        \"No structural model of the PDIK1L-SCP4 complex\",\n        \"Mechanism of nuclear recruitment unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"SCP4\", \"STK35\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}