{"gene":"ALPK2","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2018,"finding":"ALPK2 acts as a negative regulator of WNT/β-catenin signaling during cardiogenesis; loss of ALPK2 (by siRNA knockdown or CRISPR/Cas9 mutagenesis) leads to stabilization of β-catenin and increased WNT signaling, and cardiac defects can be rescued dose-dependently 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 / Strong — multiple orthogonal methods (genetic KD, CRISPR KO, phosphoproteomics, reporter assay, pharmacological rescue) in two model systems","pmids":["29888752"],"is_preprint":false},{"year":2020,"finding":"In mouse, global Alpk2 knockout (two independent CRISPR/Cas9 lines) does not produce cardiac morphological or functional defects up to one year of age, and WNT signaling is not altered in neonatal Alpk2-KO hearts, indicating that ALPK2 is dispensable for cardiac development and function in mammals.","method":"CRISPR/Cas9 global knockout (two independent mouse lines), physiological and biochemical cardiac analyses, WNT signaling assays","journal":"American Journal of Physiology. Heart and Circulatory Physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent KO lines with rigorous physiological phenotyping and molecular readouts; negative result explicitly reported","pmids":["32383995"],"is_preprint":false},{"year":2021,"finding":"ALPK2 directly interacts with DEPDC1A (identified as a downstream target); knockdown of ALPK2 suppresses bladder cancer cell proliferation, migration, and promotes apoptosis, and overexpression of DEPDC1A rescues these inhibitory effects, placing DEPDC1A downstream of ALPK2.","method":"Co-IP/interaction assays, shRNA knockdown, overexpression rescue, in vitro proliferation/migration/apoptosis assays, in vivo xenograft models","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction shown and epistasis established by rescue experiment, single lab","pmids":["34210956"],"is_preprint":false},{"year":2020,"finding":"ALPK2 knockdown in renal cell carcinoma cells inhibits proliferation, colony formation, and migration while promoting apoptosis; downstream regulation involves Akt, CDK6, Cyclin D1, and PIK3CA signaling pathways.","method":"shRNA knockdown, MTT assay, colony formation, wound-healing/Transwell assay, flow cytometry, xenograft mouse model, western blotting","journal":"Experimental Cell Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with phenotypic readouts and pathway inference by western blot only, no direct mechanistic dissection of pathway placement","pmids":["32330508"],"is_preprint":false},{"year":2020,"finding":"ALPK2 knockdown in ovarian cancer cells inhibits proliferation, induces cell cycle arrest, promotes apoptosis, and reduces migration; associated with regulation of EMT-related proteins (N-cadherin, Vimentin, Snail), anti-apoptotic proteins (Bcl-2, Bcl-w, Survivin, XIAP), and Akt/PI3K/Cyclin D1/CDK6 pathway components.","method":"Lentivirus-mediated shRNA knockdown, MTT, flow cytometry, wound-healing assay, xenograft model, western blotting","journal":"Cancer Cell International","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with pathway inference by western blot, no direct mechanistic dissection","pmids":["32595416"],"is_preprint":false},{"year":2024,"finding":"Cardiomyocyte-specific Alpk2 deficiency (tamoxifen-inducible KO mice) exacerbates cardiac diastolic dysfunction in aging and HFpEF models without affecting systolic function; Alpk2 overexpression increases phosphorylation of tropomyosin 1 and mitigates cardiac stiffness in HFpEF, identifying tropomyosin 1 as a substrate of ALPK2 relevant to diastolic regulation.","method":"Tamoxifen-inducible cardiomyocyte-specific Alpk2 KO and overexpression mice, cardiac function assessment, phosphoproteomics/western blot for tropomyosin 1 phosphorylation, HFpEF and aging models","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO and OE with defined cardiac phenotype plus identification of a phosphorylation substrate, single lab","pmids":["39556326"],"is_preprint":false}],"current_model":"ALPK2 is a cardiac-enriched atypical alpha-protein kinase that negatively regulates WNT/β-catenin signaling during cardiogenesis (established in zebrafish and hESCs), phosphorylates tropomyosin 1 to regulate cardiac diastolic function (established in mice), and interacts with DEPDC1A to promote tumor cell proliferation and survival in cancer contexts; its essential cardiac role demonstrated in zebrafish does not appear conserved in mice, where global Alpk2 knockout is dispensable for cardiac development."},"narrative":{"mechanistic_narrative":"ALPK2 is an atypical alpha-protein kinase with context-dependent roles in cardiac biology and tumor cell growth. During cardiogenesis it acts as a negative regulator of WNT/β-catenin signaling: loss of ALPK2 in hESCs and zebrafish stabilizes β-catenin and elevates WNT activity, and the resulting cardiac defects are rescued by pharmacological WNT inhibition [PMID:29888752]. This essential cardiogenic function is not conserved in mouse, where two independent global Alpk2 knockouts show normal cardiac development and unaltered WNT signaling [PMID:32383995]. In the adult mammalian heart, ALPK2 instead operates in cardiomyocytes to regulate diastolic function by phosphorylating tropomyosin 1, with cardiomyocyte-specific deletion worsening diastolic dysfunction in aging and HFpEF and overexpression reducing cardiac stiffness [PMID:39556326]. In cancer contexts, ALPK2 supports proliferation, migration, and survival; it physically interacts with DEPDC1A, and DEPDC1A re-expression rescues the anti-proliferative, pro-apoptotic effects of ALPK2 knockdown in bladder cancer cells, placing DEPDC1A downstream of ALPK2 [PMID:34210956].","teleology":[{"year":2018,"claim":"Established ALPK2's first defined mechanistic role by showing it restrains WNT/β-catenin signaling to permit normal cardiogenesis.","evidence":"siRNA/CRISPR loss-of-function in hESCs and zebrafish with phosphoproteomics, β-catenin reporter assays, and XAV939 rescue","pmids":["29888752"],"confidence":"High","gaps":["Direct kinase substrate(s) linking ALPK2 to β-catenin destabilization not identified","Whether ALPK2 acts directly on WNT pathway components or indirectly unresolved"]},{"year":2020,"claim":"Tested cross-species conservation of the cardiogenic role and found it does not hold in mammals, showing ALPK2 is dispensable for mouse cardiac development.","evidence":"Two independent CRISPR/Cas9 global knockout mouse lines with physiological phenotyping and WNT signaling readouts","pmids":["32383995"],"confidence":"High","gaps":["Does not address adult or stress-induced cardiac roles","Possible compensation or redundancy in mouse not excluded"]},{"year":2020,"claim":"Extended ALPK2 function beyond the heart by linking its knockdown to suppressed growth and survival in renal and ovarian cancer cells via Akt/PI3K/CDK6/Cyclin D1 readouts.","evidence":"shRNA knockdown with proliferation, migration, apoptosis assays, xenografts, and western blot pathway inference in RCC and ovarian cancer lines","pmids":["32330508","32595416"],"confidence":"Low","gaps":["Pathway placement inferred from western blot only, no direct mechanistic dissection","Single lab per tumor type","No direct kinase substrate identified in cancer context"]},{"year":2021,"claim":"Provided the first direct physical and epistatic partner for ALPK2 in cancer by identifying DEPDC1A as a downstream effector of its pro-tumorigenic activity.","evidence":"Co-IP interaction assays, shRNA knockdown, DEPDC1A overexpression rescue, and xenografts in bladder cancer","pmids":["34210956"],"confidence":"Medium","gaps":["Single lab without reciprocal interaction validation","Whether DEPDC1A is a phosphorylation substrate of ALPK2 unknown","Mechanism connecting the interaction to proliferation/survival undefined"]},{"year":2024,"claim":"Resolved an adult mammalian cardiac function for ALPK2 and identified its first substrate, showing it phosphorylates tropomyosin 1 to regulate diastolic stiffness.","evidence":"Tamoxifen-inducible cardiomyocyte-specific KO and overexpression mice in aging and HFpEF models with tropomyosin 1 phosphorylation readouts","pmids":["39556326"],"confidence":"Medium","gaps":["Direct in vitro demonstration of ALPK2 kinase activity on tropomyosin 1 not shown","Single lab","Relationship between diastolic role and the WNT-regulatory role undefined"]},{"year":null,"claim":"Whether ALPK2's atypical kinase activity directly phosphorylates the substrates underlying its WNT-regulatory and oncogenic phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted kinase assay defining direct substrate spectrum across contexts","Structural basis of substrate recognition unknown","Reconciliation of species-specific and context-specific roles unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[5]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["DEPDC1A","TPM1"],"other_free_text":[]}},"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). 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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 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loss of ALPK2 (by siRNA knockdown or CRISPR/Cas9 mutagenesis) leads to stabilization of β-catenin and increased WNT signaling, and cardiac defects can be rescued dose-dependently by direct WNT inhibition with XAV939.\",\n      \"method\": \"siRNA knockdown, CRISPR/Cas9 mutagenesis in hESCs and zebrafish, quantitative phosphoproteomics, β-catenin reporter assays, small-molecule rescue\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic KD, CRISPR KO, phosphoproteomics, reporter assay, pharmacological rescue) in two model systems\",\n      \"pmids\": [\"29888752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In mouse, global Alpk2 knockout (two independent CRISPR/Cas9 lines) does not produce cardiac morphological or functional defects up to one year of age, and WNT signaling is not altered in neonatal Alpk2-KO hearts, indicating that ALPK2 is dispensable for cardiac development and function in mammals.\",\n      \"method\": \"CRISPR/Cas9 global knockout (two independent mouse lines), physiological and biochemical cardiac analyses, WNT signaling assays\",\n      \"journal\": \"American Journal of Physiology. Heart and Circulatory Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent KO lines with rigorous physiological phenotyping and molecular readouts; negative result explicitly reported\",\n      \"pmids\": [\"32383995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ALPK2 directly interacts with DEPDC1A (identified as a downstream target); knockdown of ALPK2 suppresses bladder cancer cell proliferation, migration, and promotes apoptosis, and overexpression of DEPDC1A rescues these inhibitory effects, placing DEPDC1A downstream of ALPK2.\",\n      \"method\": \"Co-IP/interaction assays, shRNA knockdown, overexpression rescue, in vitro proliferation/migration/apoptosis assays, in vivo xenograft models\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction shown and epistasis established by rescue experiment, single lab\",\n      \"pmids\": [\"34210956\"],\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 regulation involves Akt, CDK6, Cyclin D1, and PIK3CA signaling pathways.\",\n      \"method\": \"shRNA knockdown, MTT assay, colony formation, wound-healing/Transwell assay, flow cytometry, xenograft mouse model, western blotting\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with phenotypic readouts and pathway inference by western blot only, no direct mechanistic dissection of pathway placement\",\n      \"pmids\": [\"32330508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ALPK2 knockdown in ovarian cancer cells inhibits proliferation, induces cell cycle arrest, promotes apoptosis, and reduces migration; associated with regulation of EMT-related proteins (N-cadherin, Vimentin, Snail), anti-apoptotic proteins (Bcl-2, Bcl-w, Survivin, XIAP), and Akt/PI3K/Cyclin D1/CDK6 pathway components.\",\n      \"method\": \"Lentivirus-mediated shRNA knockdown, MTT, flow cytometry, wound-healing assay, xenograft model, western blotting\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with pathway inference by western blot, no direct mechanistic dissection\",\n      \"pmids\": [\"32595416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cardiomyocyte-specific Alpk2 deficiency (tamoxifen-inducible KO mice) exacerbates cardiac diastolic dysfunction in aging and HFpEF models without affecting systolic function; Alpk2 overexpression increases phosphorylation of tropomyosin 1 and mitigates cardiac stiffness in HFpEF, identifying tropomyosin 1 as a substrate of ALPK2 relevant to diastolic regulation.\",\n      \"method\": \"Tamoxifen-inducible cardiomyocyte-specific Alpk2 KO and overexpression mice, cardiac function assessment, phosphoproteomics/western blot for tropomyosin 1 phosphorylation, HFpEF and aging models\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO and OE with defined cardiac phenotype plus identification of a phosphorylation substrate, single lab\",\n      \"pmids\": [\"39556326\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ALPK2 is a cardiac-enriched atypical alpha-protein kinase that negatively regulates WNT/β-catenin signaling during cardiogenesis (established in zebrafish and hESCs), phosphorylates tropomyosin 1 to regulate cardiac diastolic function (established in mice), and interacts with DEPDC1A to promote tumor cell proliferation and survival in cancer contexts; its essential cardiac role demonstrated in zebrafish does not appear conserved in mice, where global Alpk2 knockout is dispensable for cardiac development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ALPK2 is an atypical alpha-protein kinase with context-dependent roles in cardiac biology and tumor cell growth. During cardiogenesis it acts as a negative regulator of WNT/\\u03b2-catenin signaling: loss of ALPK2 in hESCs and zebrafish stabilizes \\u03b2-catenin and elevates WNT activity, and the resulting cardiac defects are rescued by pharmacological WNT inhibition [#0]. This essential cardiogenic function is not conserved in mouse, where two independent global Alpk2 knockouts show normal cardiac development and unaltered WNT signaling [#1]. In the adult mammalian heart, ALPK2 instead operates in cardiomyocytes to regulate diastolic function by phosphorylating tropomyosin 1, with cardiomyocyte-specific deletion worsening diastolic dysfunction in aging and HFpEF and overexpression reducing cardiac stiffness [#5]. In cancer contexts, ALPK2 supports proliferation, migration, and survival; it physically interacts with DEPDC1A, and DEPDC1A re-expression rescues the anti-proliferative, pro-apoptotic effects of ALPK2 knockdown in bladder cancer cells, placing DEPDC1A downstream of ALPK2 [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established ALPK2's first defined mechanistic role by showing it restrains WNT/\\u03b2-catenin signaling to permit normal cardiogenesis.\",\n      \"evidence\": \"siRNA/CRISPR loss-of-function in hESCs and zebrafish with phosphoproteomics, \\u03b2-catenin reporter assays, and XAV939 rescue\",\n      \"pmids\": [\"29888752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase substrate(s) linking ALPK2 to \\u03b2-catenin destabilization not identified\", \"Whether ALPK2 acts directly on WNT pathway components or indirectly unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Tested cross-species conservation of the cardiogenic role and found it does not hold in mammals, showing ALPK2 is dispensable for mouse cardiac development.\",\n      \"evidence\": \"Two independent CRISPR/Cas9 global knockout mouse lines with physiological phenotyping and WNT signaling readouts\",\n      \"pmids\": [\"32383995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address adult or stress-induced cardiac roles\", \"Possible compensation or redundancy in mouse not excluded\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended ALPK2 function beyond the heart by linking its knockdown to suppressed growth and survival in renal and ovarian cancer cells via Akt/PI3K/CDK6/Cyclin D1 readouts.\",\n      \"evidence\": \"shRNA knockdown with proliferation, migration, apoptosis assays, xenografts, and western blot pathway inference in RCC and ovarian cancer lines\",\n      \"pmids\": [\"32330508\", \"32595416\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement inferred from western blot only, no direct mechanistic dissection\", \"Single lab per tumor type\", \"No direct kinase substrate identified in cancer context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the first direct physical and epistatic partner for ALPK2 in cancer by identifying DEPDC1A as a downstream effector of its pro-tumorigenic activity.\",\n      \"evidence\": \"Co-IP interaction assays, shRNA knockdown, DEPDC1A overexpression rescue, and xenografts in bladder cancer\",\n      \"pmids\": [\"34210956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without reciprocal interaction validation\", \"Whether DEPDC1A is a phosphorylation substrate of ALPK2 unknown\", \"Mechanism connecting the interaction to proliferation/survival undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved an adult mammalian cardiac function for ALPK2 and identified its first substrate, showing it phosphorylates tropomyosin 1 to regulate diastolic stiffness.\",\n      \"evidence\": \"Tamoxifen-inducible cardiomyocyte-specific KO and overexpression mice in aging and HFpEF models with tropomyosin 1 phosphorylation readouts\",\n      \"pmids\": [\"39556326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro demonstration of ALPK2 kinase activity on tropomyosin 1 not shown\", \"Single lab\", \"Relationship between diastolic role and the WNT-regulatory role undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether ALPK2's atypical kinase activity directly phosphorylates the substrates underlying its WNT-regulatory and oncogenic phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted kinase assay defining direct substrate spectrum across contexts\", \"Structural basis of substrate recognition unknown\", \"Reconciliation of species-specific and context-specific roles unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DEPDC1A\", \"TPM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":4,"faith_pct":75.0}}