Affinage

ALPK2

Alpha-protein kinase 2 · UniProt Q86TB3

Length
2170 aa
Mass
237.0 kDa
Annotated
2026-04-28
53 papers in source corpus 7 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2018 High

    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

    PMID:29888752

    Open questions at the time
    • 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
  2. 2020 High

    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

    PMID:32383995

    Open questions at the time
    • 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
  3. 2021 Medium

    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

    PMID:34210956

    Open questions at the time
    • 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
  4. 2024 Medium

    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

    PMID:39556326

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2
Pathway
R-HSA-162582 Signal Transduction 1 R-HSA-397014 Muscle contraction 1
Partners
DEPDC1ATPM1

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 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. siRNA knockdown, CRISPR/Cas9 mutagenesis in hESCs and zebrafish, quantitative phosphoproteomics, β-catenin reporter assays, small-molecule rescue iScience High 29888752
2020 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. CRISPR/Cas9 global knockout mouse generation, physiological and biochemical cardiac analyses, WNT signaling assays American journal of physiology. Heart and circulatory physiology High 32383995
2021 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. Co-IP (direct interaction), shRNA knockdown, overexpression rescue experiments, in vitro proliferation/apoptosis/migration assays, in vivo xenograft Cell death & disease Medium 34210956
2024 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. Tamoxifen-inducible cardiomyocyte-specific Alpk2-knockout mice, Alpk2-overexpressing mice, phosphorylation assays, HFpEF and aging models FASEB journal Medium 39556326
2020 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. shRNA knockdown, MTT assay, colony formation, wound-healing, flow cytometry, xenograft mouse model, western blot pathway analysis Experimental cell research Low 32330508
2020 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. Lentivirus-mediated shRNA knockdown, MTT assay, flow cytometry, wound-healing assay, xenograft model, western blot Cancer cell international Low 32595416
2021 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. CircRNA silencing, miRNA target assays, ALPK2 overexpression rescue, in vitro RCC cell assays Cell cycle Low 34705617

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Inventory and functional characterization of the HAK potassium transporters of rice. Plant physiology 194 12376644
2019 A HAK family Na+ transporter confers natural variation of salt tolerance in maize. Nature plants 144 31819228
2017 Plant HAK/KUP/KT K+ transporters: Function and regulation. Seminars in cell & developmental biology 121 28711523
2002 The expression of HAK-type K(+) transporters is regulated in response to salinity stress in common ice plant. Plant physiology 74 12177462
2016 Uneven HAK/KUP/KT Protein Diversity Among Angiosperms: Species Distribution and Perspectives. Frontiers in plant science 66 26904084
2012 Genome-wide analysis and identification of HAK potassium transporter gene family in maize (Zea mays L.). Molecular biology reports 61 22711305
2009 Molecular evolution and functional divergence of HAK potassium transporter gene family in rice (Oryza sativa L.). Journal of genetics and genomics = Yi chuan xue bao 46 19302972
2018 Genome-Wide Identification and Analysis of HAK/KUP/KT Potassium Transporters Gene Family in Wheat (Triticum aestivum L.). International journal of molecular sciences 44 30544665
2021 Identification and characterization of HAK/KUP/KT potassium transporter gene family in barley and their expression under abiotic stress. BMC genomics 33 33932999
2010 AtKUP/HAK/KT9, a K+ transporter from Arabidopsis thaliana, mediates Cs+ uptake in Escherichia coli. Bioscience, biotechnology, and biochemistry 31 20057125
2020 HAK/KUP/KT family potassium transporter genes are involved in potassium deficiency and stress responses in tea plants (Camellia sinensis L.): expression and functional analysis. BMC genomics 29 32791963
2018 ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells. iScience 28 29888752
2012 Genome-wide and molecular evolution analysis of the Poplar KT/HAK/KUP potassium transporter gene family. Ecology and evolution 27 22957200
2000 Individual functions of the HAK and TRK potassium transporters of Schwanniomyces occidentalis. Molecular microbiology 27 10931360
2018 Genome-wide identification, evolution, and expression analysis of the KT/HAK/KUP family in pear. Genome 24 30130425
2015 Genome-wide analysis and identification of KT/HAK/KUP potassium transporter gene family in peach (Prunus persica). Genetics and molecular research : GMR 21 25730015
2020 Characterization and Expression of KT/HAK/KUP Transporter Family Genes in Willow under Potassium Deficiency, Drought, and Salt Stresses. BioMed research international 20 32596286
2018 Characterization of rice KT/HAK/KUP potassium transporters and K+ uptake by HAK1 from Oryza sativa. Plant biotechnology (Tokyo, Japan) 19 31819712
2011 Functional HAK/KUP/KT-like potassium transporter encoded by chlorella viruses. The Plant journal : for cell and molecular biology 19 21848655
2020 Genome-wide characterization and expression analysis of HAK K+ transport family in Ipomoea. 3 Biotech 14 33269187
2020 Genome-Wide Survey and Expression Analysis of the KT/HAK/KUP Family in Brassica napus and Its Potential Roles in the Response to K+ Deficiency. International journal of molecular sciences 14 33322211
2024 Genome-wide identification and expression analysis of the HAK/KUP/KT gene family in Moso bamboo. Frontiers in plant science 12 38595761
2021 ALPK2 acts as tumor promotor in development of bladder cancer through targeting DEPDC1A. Cell death & disease 12 34210956
2019 Genome-wide analysis of the HAK potassium transporter gene family reveals asymmetrical evolution in tobacco (Nicotiana tabacum). Genome 11 30865850
2023 Characterization of HAK protein family in Casuarina equisetifolia and the positive regulatory role of CeqHAK6 and CeqHAK11 genes in response to salt tolerance. Frontiers in plant science 10 36816483
1999 Establishment and characterization of a new human hepatocellular carcinoma cell line, HAK-3, and its response to growth factors. International journal of oncology 10 10493947
1997 A new human hepatocellular carcinoma cell line (HAK-2) forms various structures in collagen gel matrices. Human cell 10 9436038
2021 Hsa_circ_0065217 promotes growth and metastasis of renal cancer through regulating the miR-214-3p-ALPK2 axis. Cell cycle (Georgetown, Tex.) 9 34705617
2020 Atypical ALPK2 kinase is not essential for cardiac development and function. American journal of physiology. Heart and circulatory physiology 9 32383995
2023 Phylogenetic, structural, functional characterisation and effect of exogenous spermidine on rice (Oryza sativa) HAK transporters under salt stress. Functional plant biology : FPB 8 36031595
2020 Knockdown of ALPK2 inhibits the development and progression of Ovarian Cancer. Cancer cell international 8 32595416
2020 Knockdown of ALPK2 blocks development and progression of renal cell carcinoma. Experimental cell research 7 32330508
2022 Transcriptome-wide identification and expression analysis of the KT/HAK/KUP family in Salicornia europaea L. under varied NaCl and KCl treatments. PeerJ 6 35261820
2022 Genome-wide characterization and expression analysis of the HAK gene family in response to abiotic stresses in Medicago. BMC genomics 6 36456911
2025 A SnRK2-HAK regulatory module confers natural variation of salt tolerance in maize. Nature communications 5 40301371
2022 Genome-wide identification, characterization and expression analysis of HAK genes and decoding their role in responding to potassium deficiency and abiotic stress in Medicago truncatula. PeerJ 5 36168431
2021 A genomic variant of ALPK2 is associated with increased liver fibrosis risk in HIV/HCV coinfected women. PloS one 4 33705408
2020 Genome-Wide Identification and Expression Pattern Analysis of the HAK/KUP/KT Gene Family of Cotton in Fiber Development and Under Stresses. Frontiers in genetics 4 33329704
2025 Genome-wide identification, characterization and expression pattern analysis of HAK/KUP/KT potassium transporter gene family in potato. Frontiers in plant science 3 39886687
2025 The Role of Potassium and KUP/KT/HAK Transporters in Regulating Strawberry (Fragaria × ananassa Duch.) Fruit Development. Plants (Basel, Switzerland) 3 40733478
2024 Genome-wide survey of KT/HAK/KUP genes in the genus Citrullus and analysis of their involvement in K+-deficiency and drought stress responses in between C. lanatus and C. amarus. BMC genomics 3 39237905
2022 Genome-wide identification and expression analysis of HAK/KUP/KT potassium transporter provides insights into genes involved in responding to potassium deficiency and salt stress in pepper (Capsicum annuum L.). 3 Biotech 3 35251880
2025 Genome wide identification and functional analyses of HAK family potassium transporter genes in passion fruit (Passiflora edulis Sims) in response to potassium deficiency and stress responses. Plant physiology and biochemistry : PPB 2 40381362
2023 Genome wide identification, structural characterization and phylogenetic analysis of High-Affinity potassium (HAK) ion transporters in common bean (Phaseolus vulgaris L.). BMC genomic data 2 37964195
2022 Identification and stress function verification of the HAK/KUP/KT family in Gossypium hirsutum. Gene 2 35085713
1996 [The cytogenetic study of established Syrian hamster cell lines. II. A comparative analysis of the karyotypes of cell lines HaK, CER and BHK-21 (C-13)]. Tsitologiia 2 9027007
1981 Evaluation and comparative studies of inactivated rabies vaccines obtained in the heterologous diploid and polyploid cells (HAK, BHK and VERO). Developments in biological standardization 2 7341292
2024 ALPK2 prevents cardiac diastolic dysfunction in heart failure with preserved ejection fraction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1 39556326
2021 Corrigendum: Genome-Wide Identification and Expression Pattern Analysis of the HAK/KUP/KT Gene Family of Cotton in Fiber Development and Under Stresses. Frontiers in genetics 1 34354731
1981 [Comparison of inactivated rabies vaccines obtained from diploid and polyploid heterologous cells (Hak, BHK, and Vero)]. Archives de l'Institut Pasteur de Tunis 1 7316614
2026 HAK-actin, a U-ExM-compatible probe to image the actin cytoskeleton. Cell reports methods 0 41997153
2025 Identification, classification, and stress-responsive regulation of HAK family genes in poplar. Frontiers in plant science 0 41323314
2012 [Isolation of the promoter region of HAK gene from Aeluropus littoralis and functional analysis in rice]. Yi chuan = Hereditas 0 22698746