{"gene":"ALPK2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2018,"finding":"ALPK2 acts as a negative regulator of WNT/β-catenin signaling during cardiomyocyte differentiation; loss of ALPK2 leads to stabilization of β-catenin and increased WNT signaling, and cardiac defects from ALPK2 depletion are rescued by direct WNT inhibition with XAV939.","method":"siRNA knockdown, CRISPR/Cas9 mutagenesis in hESCs and zebrafish, quantitative phosphoproteomics, β-catenin reporter assays, small-molecule rescue","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (CRISPR KO, phosphoproteomics, reporter assay, pharmacological rescue) in two model systems","pmids":["29888752"],"is_preprint":false},{"year":2020,"finding":"Global Alpk2-knockout mice show normal cardiac function and morphology up to one year of age, and no altered WNT signaling in neonatal hearts, indicating ALPK2 is dispensable for cardiac development in the murine model despite its role in zebrafish.","method":"CRISPR/Cas9 global knockout mouse generation, physiological and biochemical cardiac analyses, WNT signaling assays","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 1-2 — two independent Alpk2-gKO mouse lines with comprehensive functional and molecular analyses","pmids":["32383995"],"is_preprint":false},{"year":2021,"finding":"ALPK2 directly interacts with DEPDC1A, and ALPK2 promotes bladder cancer development through regulation of DEPDC1A; overexpression of DEPDC1A rescues the inhibitory effects of ALPK2 knockdown on bladder cancer cell malignancy.","method":"Co-IP (direct interaction), shRNA knockdown, overexpression rescue experiments, in vitro proliferation/apoptosis/migration assays, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct interaction demonstrated plus epistasis rescue, but single lab","pmids":["34210956"],"is_preprint":false},{"year":2024,"finding":"ALPK2 is a cardiac-specific atypical kinase that phosphorylates tropomyosin 1, a regulator of myosin-actin binding; cardiomyocyte-specific Alpk2 deficiency exacerbates cardiac diastolic dysfunction in aging and HFpEF models, while Alpk2 overexpression increases tropomyosin 1 phosphorylation and mitigates cardiac stiffness.","method":"Tamoxifen-inducible cardiomyocyte-specific Alpk2-knockout mice, Alpk2-overexpressing mice, phosphorylation assays, HFpEF and aging models","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO and OE with defined molecular substrate (tropomyosin 1 phosphorylation) and functional phenotype, single lab","pmids":["39556326"],"is_preprint":false},{"year":2020,"finding":"ALPK2 knockdown in renal cell carcinoma cells inhibits proliferation, colony formation, and migration while promoting apoptosis; downstream effectors include Akt, CDK6, Cyclin D1, and PIK3CA signaling.","method":"shRNA knockdown, MTT assay, colony formation, wound-healing, flow cytometry, xenograft mouse model, western blot pathway analysis","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 — loss-of-function with phenotype and pathway markers, but no direct biochemical mechanism established; single lab","pmids":["32330508"],"is_preprint":false},{"year":2020,"finding":"ALPK2 knockdown in ovarian cancer cells inhibits proliferation and migration, promotes apoptosis, and arrests the cell cycle; downstream effects include regulation of EMT-related proteins (N-cadherin, Vimentin, Snail), apoptosis proteins (Bcl-2, Survivin, XIAP), and Akt/PIK3CA/CDK6/Cyclin D1 pathway.","method":"Lentivirus-mediated shRNA knockdown, MTT assay, flow cytometry, wound-healing assay, xenograft model, western blot","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 — loss-of-function with phenotype and signaling readouts, but no direct biochemical mechanism; single lab","pmids":["32595416"],"is_preprint":false},{"year":2021,"finding":"hsa_circ_0065217 promotes ALPK2 expression by acting as a competing endogenous RNA (ceRNA) sponging miR-214-3p; ALPK2 overexpression reverses the effects of hsa_circ_0065217 knockdown on renal cell carcinoma malignancy.","method":"CircRNA silencing, miRNA target assays, ALPK2 overexpression rescue, in vitro RCC cell assays","journal":"Cell cycle","confidence":"Low","confidence_rationale":"Tier 3 — ceRNA regulatory axis established by functional rescue, single lab","pmids":["34705617"],"is_preprint":false}],"current_model":"ALPK2 is a cardiac-enriched atypical alpha-kinase that negatively regulates WNT/β-catenin signaling during cardiomyocyte differentiation (in zebrafish and hESCs), phosphorylates tropomyosin 1 to regulate cardiac diastolic function (in mice), and interacts with DEPDC1A to promote tumor progression in bladder cancer, while its essentiality for cardiac development appears to have been lost in mammals."},"narrative":{"teleology":[{"year":2018,"claim":"Establishing ALPK2 as a signaling regulator in cardiogenesis resolved its functional role beyond sequence-based kinase classification, showing it negatively regulates WNT/β-catenin signaling during cardiomyocyte differentiation.","evidence":"siRNA knockdown and CRISPR/Cas9 mutagenesis in hESCs and zebrafish, phosphoproteomics, β-catenin reporter assays, and pharmacological rescue with XAV939","pmids":["29888752"],"confidence":"High","gaps":["Direct kinase substrate(s) mediating WNT inhibition were not identified","Whether ALPK2 phosphorylates β-catenin or an upstream component was not determined","Mammalian in vivo validation of WNT-regulatory role was lacking"]},{"year":2020,"claim":"Testing whether the zebrafish cardiac phenotype translates to mammals revealed that global Alpk2 knockout mice have normal cardiac function and no altered WNT signaling, establishing species-specific dispensability.","evidence":"Two independent CRISPR/Cas9-generated Alpk2-knockout mouse lines with comprehensive cardiac physiological and molecular analyses","pmids":["32383995"],"confidence":"High","gaps":["Compensatory mechanisms by related kinases were not investigated","Conditional or stress-dependent cardiac phenotypes were not tested at this stage","Whether ALPK2 has non-cardiac roles in mice was unexplored"]},{"year":2021,"claim":"Identification of DEPDC1A as a direct interaction partner expanded ALPK2 function beyond the heart, linking it to bladder cancer cell proliferation and migration through epistatic rescue experiments.","evidence":"Co-immunoprecipitation, shRNA knockdown, DEPDC1A overexpression rescue, in vitro and xenograft assays in bladder cancer cells","pmids":["34210956"],"confidence":"Medium","gaps":["Whether ALPK2 phosphorylates DEPDC1A directly was not tested","Single-lab finding without independent replication","Mechanism by which ALPK2–DEPDC1A interaction promotes tumor progression is undefined"]},{"year":2024,"claim":"Identification of tropomyosin 1 as a direct ALPK2 phosphorylation substrate resolved a long-standing gap in its kinase activity and linked it to regulation of cardiac diastolic function.","evidence":"Tamoxifen-inducible cardiomyocyte-specific Alpk2 knockout and overexpression mice, phosphorylation assays, aging and HFpEF disease models","pmids":["39556326"],"confidence":"Medium","gaps":["Specific phosphorylation site(s) on tropomyosin 1 and structural consequences were not fully characterized","Single-lab finding; independent confirmation needed","Whether tropomyosin 1 is the sole cardiac substrate or one of several is unknown"]},{"year":null,"claim":"A complete substrate repertoire for ALPK2 kinase activity remains undefined, and how its WNT-regulatory and sarcomeric functions are integrated or independently regulated in different cellular contexts is unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the ALPK2 alpha-kinase domain exists","Relationship between WNT-regulatory function and tropomyosin 1 phosphorylation is unknown","Whether ALPK2 kinase activity is required for its oncogenic roles has not been tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[3]}],"complexes":[],"partners":["TPM1","DEPDC1A"],"other_free_text":[]},"mechanistic_narrative":"ALPK2 is a cardiac-enriched atypical alpha-kinase that regulates cardiomyocyte signaling and sarcomeric function. During cardiomyocyte differentiation, ALPK2 negatively regulates WNT/β-catenin signaling; its depletion stabilizes β-catenin and impairs cardiac specification in zebrafish and human embryonic stem cells, though global Alpk2 knockout in mice reveals dispensability for murine cardiac development [PMID:29888752, PMID:32383995]. In adult cardiomyocytes, ALPK2 phosphorylates tropomyosin 1 to regulate myosin–actin interactions, and cardiomyocyte-specific Alpk2 deficiency exacerbates diastolic dysfunction in aging and heart failure with preserved ejection fraction models [PMID:39556326]. ALPK2 also interacts with DEPDC1A to promote bladder cancer cell proliferation and migration [PMID:34210956]."},"prefetch_data":{"uniprot":{"accession":"Q86TB3","full_name":"Alpha-protein kinase 2","aliases":["Heart alpha-protein kinase"],"length_aa":2170,"mass_kda":237.0,"function":"Protein kinase that recognizes phosphorylation sites in which the surrounding peptides have an alpha-helical conformation (PubMed:10021370). Regulates cardiac development and cardiomyocyte differentiation by negatively regulating Wnt/beta-catenin signaling (PubMed:29888752)","subcellular_location":"Basolateral cell membrane","url":"https://www.uniprot.org/uniprotkb/Q86TB3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ALPK2","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/ALPK2","total_profiled":1310},"omim":[{"mim_id":"619965","title":"ALPHA KINASE 2; ALPK2","url":"https://www.omim.org/entry/619965"},{"mim_id":"617608","title":"ALPHA KINASE 3; ALPK3","url":"https://www.omim.org/entry/617608"},{"mim_id":"607347","title":"ALPHA KINASE 1; ALPK1","url":"https://www.omim.org/entry/607347"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"heart muscle","ntpm":39.2},{"tissue":"skeletal muscle","ntpm":35.9},{"tissue":"tongue","ntpm":31.0}],"url":"https://www.proteinatlas.org/search/ALPK2"},"hgnc":{"alias_symbol":["HAK"],"prev_symbol":[]},"alphafold":{"accession":"Q86TB3","domains":[{"cath_id":"2.60.40.10","chopping":"11-107","consensus_level":"medium","plddt":82.5537,"start":11,"end":107},{"cath_id":"2.60.40.10","chopping":"1786-1886","consensus_level":"medium","plddt":80.5074,"start":1786,"end":1886}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86TB3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86TB3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86TB3-F1-predicted_aligned_error_v6.png","plddt_mean":40.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ALPK2","jax_strain_url":"https://www.jax.org/strain/search?query=ALPK2"},"sequence":{"accession":"Q86TB3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86TB3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86TB3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86TB3"}},"corpus_meta":[{"pmid":"12376644","id":"PMC_12376644","title":"Inventory 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Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — two independent Alpk2-gKO mouse lines with comprehensive functional and molecular analyses\",\n      \"pmids\": [\"32383995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ALPK2 directly interacts with DEPDC1A, and ALPK2 promotes bladder cancer development through regulation of DEPDC1A; overexpression of DEPDC1A rescues the inhibitory effects of ALPK2 knockdown on bladder cancer cell malignancy.\",\n      \"method\": \"Co-IP (direct interaction), shRNA knockdown, overexpression rescue experiments, in vitro proliferation/apoptosis/migration assays, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct interaction demonstrated plus epistasis rescue, but single lab\",\n      \"pmids\": [\"34210956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALPK2 is a cardiac-specific atypical kinase that phosphorylates tropomyosin 1, a regulator of myosin-actin binding; cardiomyocyte-specific Alpk2 deficiency exacerbates cardiac diastolic dysfunction in aging and HFpEF models, while Alpk2 overexpression increases tropomyosin 1 phosphorylation and mitigates cardiac stiffness.\",\n      \"method\": \"Tamoxifen-inducible cardiomyocyte-specific Alpk2-knockout mice, Alpk2-overexpressing mice, phosphorylation assays, HFpEF and aging models\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO and OE with defined molecular substrate (tropomyosin 1 phosphorylation) and functional phenotype, single lab\",\n      \"pmids\": [\"39556326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ALPK2 knockdown in renal cell carcinoma cells inhibits proliferation, colony formation, and migration while promoting apoptosis; downstream effectors include Akt, CDK6, Cyclin D1, and PIK3CA signaling.\",\n      \"method\": \"shRNA knockdown, MTT assay, colony formation, wound-healing, flow cytometry, xenograft mouse model, western blot pathway analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function with phenotype and pathway markers, but no direct biochemical mechanism established; single lab\",\n      \"pmids\": [\"32330508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ALPK2 knockdown in ovarian cancer cells inhibits proliferation and migration, promotes apoptosis, and arrests the cell cycle; downstream effects include regulation of EMT-related proteins (N-cadherin, Vimentin, Snail), apoptosis proteins (Bcl-2, Survivin, XIAP), and Akt/PIK3CA/CDK6/Cyclin D1 pathway.\",\n      \"method\": \"Lentivirus-mediated shRNA knockdown, MTT assay, flow cytometry, wound-healing assay, xenograft model, western blot\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — loss-of-function with phenotype and signaling readouts, but no direct biochemical mechanism; single lab\",\n      \"pmids\": [\"32595416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"hsa_circ_0065217 promotes ALPK2 expression by acting as a competing endogenous RNA (ceRNA) sponging miR-214-3p; ALPK2 overexpression reverses the effects of hsa_circ_0065217 knockdown on renal cell carcinoma malignancy.\",\n      \"method\": \"CircRNA silencing, miRNA target assays, ALPK2 overexpression rescue, in vitro RCC cell assays\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ceRNA regulatory axis established by functional rescue, single lab\",\n      \"pmids\": [\"34705617\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ALPK2 is a cardiac-enriched atypical alpha-kinase that negatively regulates WNT/β-catenin signaling during cardiomyocyte differentiation (in zebrafish and hESCs), phosphorylates tropomyosin 1 to regulate cardiac diastolic function (in mice), and interacts with DEPDC1A to promote tumor progression in bladder cancer, while its essentiality for cardiac development appears to have been lost in mammals.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ALPK2 is a cardiac-enriched atypical alpha-kinase that regulates cardiomyocyte signaling and sarcomeric function. During cardiomyocyte differentiation, ALPK2 negatively regulates WNT/β-catenin signaling; its depletion stabilizes β-catenin and impairs cardiac specification in zebrafish and human embryonic stem cells, though global Alpk2 knockout in mice reveals dispensability for murine cardiac development [PMID:29888752, PMID:32383995]. In adult cardiomyocytes, ALPK2 phosphorylates tropomyosin 1 to regulate myosin–actin interactions, and cardiomyocyte-specific Alpk2 deficiency exacerbates diastolic dysfunction in aging and heart failure with preserved ejection fraction models [PMID:39556326]. ALPK2 also interacts with DEPDC1A to promote bladder cancer cell proliferation and migration [PMID:34210956].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing ALPK2 as a signaling regulator in cardiogenesis resolved its functional role beyond sequence-based kinase classification, showing it negatively regulates WNT/β-catenin signaling during cardiomyocyte differentiation.\",\n      \"evidence\": \"siRNA knockdown and CRISPR/Cas9 mutagenesis in hESCs and zebrafish, phosphoproteomics, β-catenin reporter assays, and pharmacological rescue with XAV939\",\n      \"pmids\": [\"29888752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct kinase substrate(s) mediating WNT inhibition were not identified\",\n        \"Whether ALPK2 phosphorylates β-catenin or an upstream component was not determined\",\n        \"Mammalian in vivo validation of WNT-regulatory role was lacking\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Testing whether the zebrafish cardiac phenotype translates to mammals revealed that global Alpk2 knockout mice have normal cardiac function and no altered WNT signaling, establishing species-specific dispensability.\",\n      \"evidence\": \"Two independent CRISPR/Cas9-generated Alpk2-knockout mouse lines with comprehensive cardiac physiological and molecular analyses\",\n      \"pmids\": [\"32383995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Compensatory mechanisms by related kinases were not investigated\",\n        \"Conditional or stress-dependent cardiac phenotypes were not tested at this stage\",\n        \"Whether ALPK2 has non-cardiac roles in mice was unexplored\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of DEPDC1A as a direct interaction partner expanded ALPK2 function beyond the heart, linking it to bladder cancer cell proliferation and migration through epistatic rescue experiments.\",\n      \"evidence\": \"Co-immunoprecipitation, shRNA knockdown, DEPDC1A overexpression rescue, in vitro and xenograft assays in bladder cancer cells\",\n      \"pmids\": [\"34210956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ALPK2 phosphorylates DEPDC1A directly was not tested\",\n        \"Single-lab finding without independent replication\",\n        \"Mechanism by which ALPK2–DEPDC1A interaction promotes tumor progression is undefined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of tropomyosin 1 as a direct ALPK2 phosphorylation substrate resolved a long-standing gap in its kinase activity and linked it to regulation of cardiac diastolic function.\",\n      \"evidence\": \"Tamoxifen-inducible cardiomyocyte-specific Alpk2 knockout and overexpression mice, phosphorylation assays, aging and HFpEF disease models\",\n      \"pmids\": [\"39556326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific phosphorylation site(s) on tropomyosin 1 and structural consequences were not fully characterized\",\n        \"Single-lab finding; independent confirmation needed\",\n        \"Whether tropomyosin 1 is the sole cardiac substrate or one of several is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A complete substrate repertoire for ALPK2 kinase activity remains undefined, and how its WNT-regulatory and sarcomeric functions are integrated or independently regulated in different cellular contexts is unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the ALPK2 alpha-kinase domain exists\",\n        \"Relationship between WNT-regulatory function and tropomyosin 1 phosphorylation is unknown\",\n        \"Whether ALPK2 kinase activity is required for its oncogenic roles has not been tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TPM1\", \"DEPDC1A\"],\n    \"other_free_text\": []\n  }\n}\n```"}