Affinage

ALPK2

Alpha-protein kinase 2 · UniProt Q86TB3

Length
2170 aa
Mass
237.0 kDa
Annotated
2026-06-09
48 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/4 claims corpus-supported (75%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2018 High

    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

    PMID:29888752

    Open questions at the time
    • Direct kinase substrate(s) linking ALPK2 to β-catenin destabilization not identified
    • Whether ALPK2 acts directly on WNT pathway components or indirectly unresolved
  2. 2020 High

    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

    PMID:32383995

    Open questions at the time
    • Does not address adult or stress-induced cardiac roles
    • Possible compensation or redundancy in mouse not excluded
  3. 2020 Low

    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

    PMID:32330508 PMID:32595416

    Open questions at the time
    • Pathway placement inferred from western blot only, no direct mechanistic dissection
    • Single lab per tumor type
    • No direct kinase substrate identified in cancer context
  4. 2021 Medium

    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

    PMID:34210956

    Open questions at the time
    • Single lab without reciprocal interaction validation
    • Whether DEPDC1A is a phosphorylation substrate of ALPK2 unknown
    • Mechanism connecting the interaction to proliferation/survival undefined
  5. 2024 Medium

    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

    PMID:39556326

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether ALPK2's atypical kinase activity directly phosphorylates the substrates underlying its WNT-regulatory and oncogenic phenotypes remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 1 GO:0140096 catalytic activity, acting on a protein 1
Pathway
R-HSA-162582 Signal Transduction 1
Partners
DEPDC1ATPM1

Evidence

Reading pass · 6 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 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. siRNA knockdown, CRISPR/Cas9 mutagenesis in hESCs and zebrafish, quantitative phosphoproteomics, β-catenin reporter assays, small-molecule rescue iScience High 29888752
2020 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. CRISPR/Cas9 global knockout (two independent mouse lines), physiological and biochemical cardiac analyses, WNT signaling assays American Journal of Physiology. Heart and Circulatory Physiology High 32383995
2021 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. Co-IP/interaction assays, shRNA knockdown, overexpression rescue, in vitro proliferation/migration/apoptosis assays, in vivo xenograft models Cell Death & Disease Medium 34210956
2020 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. shRNA knockdown, MTT assay, colony formation, wound-healing/Transwell assay, flow cytometry, xenograft mouse model, western blotting Experimental Cell Research Low 32330508
2020 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. Lentivirus-mediated shRNA knockdown, MTT, flow cytometry, wound-healing assay, xenograft model, western blotting Cancer Cell International Low 32595416
2024 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. Tamoxifen-inducible cardiomyocyte-specific Alpk2 KO and overexpression mice, cardiac function assessment, phosphoproteomics/western blot for tropomyosin 1 phosphorylation, HFpEF and aging models FASEB Journal Medium 39556326

Source papers

Stage 0 corpus · 48 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 149 31819228
2017 Plant HAK/KUP/KT K+ transporters: Function and regulation. Seminars in cell & developmental biology 123 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 67 26904084
2021 Identification and characterization of HAK/KUP/KT potassium transporter gene family in barley and their expression under abiotic stress. BMC genomics 33 33932999
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 30 32791963
2018 ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells. iScience 29 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
2020 Characterization and Expression of KT/HAK/KUP Transporter Family Genes in Willow under Potassium Deficiency, Drought, and Salt Stresses. BioMed research international 21 32596286
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
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
2021 ALPK2 acts as tumor promotor in development of bladder cancer through targeting DEPDC1A. Cell death & disease 13 34210956
2024 Genome-wide identification and expression analysis of the HAK/KUP/KT gene family in Moso bamboo. Frontiers in plant science 12 38595761
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 11 36816483
2019 Genome-wide analysis of the HAK potassium transporter gene family reveals asymmetrical evolution in tobacco (Nicotiana tabacum). Genome 11 30865850
2020 Knockdown of ALPK2 inhibits the development and progression of Ovarian Cancer. Cancer cell international 10 32595416
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 Knockdown of ALPK2 blocks development and progression of renal cell carcinoma. Experimental cell research 9 32330508
2020 Atypical ALPK2 kinase is not essential for cardiac development and function. American journal of physiology. Heart and circulatory physiology 9 32383995
2025 A SnRK2-HAK regulatory module confers natural variation of salt tolerance in maize. Nature communications 7 40301371
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
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
2025 Genome-wide identification, characterization and expression pattern analysis of HAK/KUP/KT potassium transporter gene family in potato. Frontiers in plant science 4 39886687
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 4 39237905
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 The Role of Potassium and KUP/KT/HAK Transporters in Regulating Strawberry (Fragaria × ananassa Duch.) Fruit Development. Plants (Basel, Switzerland) 3 40733478
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
2026 Investigating the Role of ALPK2 in Endometrial Cancer Progression: From Biological Function to Clinical Translation. Reproductive sciences (Thousand Oaks, Calif.) 0 42082823
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

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