Affinage

PSKH1

Serine/threonine-protein kinase H1 · UniProt P11801

Length
424 aa
Mass
48.0 kDa
Annotated
2026-06-10
17 papers in source corpus 10 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSKH1 is a calmodulin-regulated protein serine kinase of the CAMK family whose subcellular targeting and catalytic output are tightly controlled to support membrane organization and ciliary function (PMID:11087665, PMID:14644153, PMID:39964718). The enzyme autophosphorylates on C-terminal serines in an intermolecular reaction and is allosterically tuned by calcium-sensing partners: Ca2+/calmodulin and UNC119B engage and activate the kinase domain, whereas the ER Ca2+-sensor Reticulocalbin-3 suppresses its activity, even though PSKH1 lacks a canonical CaM-binding motif (PMID:11087665, PMID:39964718). Dual N-terminal acylation—myristoylation on Gly2 and palmitoylation on Cys3—directs PSKH1 to the Golgi apparatus and, in the absence of palmitoylation, to ER membranes; the integrity of this targeting and the kinase domain is required for normal Golgi structure (PMID:14644153). PSKH1 also localizes to nuclear splicing factor compartments and centrosomes, where it reorganizes SR proteins and stimulates pre-mRNA splicing of an E1A minigene by a kinase-independent, indirect mechanism that does not involve direct phosphorylation of ASF/SF2 (PMID:11087665, PMID:12466556). Loss-of-function PSKH1 mutations that abolish catalytic activity cause a hepatorenal ciliopathy in humans, with patient fibroblasts and a homozygous mutant mouse showing abnormally long cilia and aberrant ciliary transport, establishing that PSKH1 kinase activity is required for normal ciliogenesis (PMID:39132680). In cancer contexts, PSKH1 promotes cell growth and is positioned upstream of p38/MAPK signaling (PMID:36936027).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2000 Medium

    Establishing PSKH1 as an autoregulated, calcium-responsive kinase answered whether and how its catalytic activity is controlled.

    Evidence In vitro kinase assay with immunoisolated PSKH1 and Ca2+/CaM addition

    PMID:11087665

    Open questions at the time
    • No physiological substrate identified
    • Effect of Ca2+/CaM was repression of autophosphorylation, later refined as allosteric activation by other studies
  2. 2000 Medium

    Mapping endogenous PSKH1 to Golgi, centrosomes, and nuclear speckles defined the compartments where it might act and linked it to stress responses.

    Evidence Indirect immunofluorescence in COS-1 cells with Brefeldin A and osmotic stress

    PMID:11087665

    Open questions at the time
    • Functional consequence at each compartment unresolved
    • Mechanism of centrosomal enrichment under stress unknown
  3. 2002 Medium

    Linking PSKH1 to splicing factor compartments and SR protein dynamics addressed whether it participates in pre-mRNA processing, revealing a kinase-independent, indirect role.

    Evidence Immunofluorescence, SR co-expression, E1A minigene splicing, GST kinase assay, and domain truncation in HeLa cells

    PMID:12466556

    Open questions at the time
    • Direct nuclear substrate not identified
    • Mechanism linking cytoplasmic/Golgi kinase to nuclear SR redistribution unclear
    • ASF/SF2 is not a direct substrate
  4. 2003 High

    Identifying dual acylation as the membrane-targeting determinant explained how PSKH1 is positioned at the Golgi and ER and tied it to organelle integrity.

    Evidence Acylation assays, organelle marker co-localization, immunoelectron microscopy, fractionation, and site-directed mutagenesis

    PMID:14644153

    Open questions at the time
    • Whether Golgi disassembly reflects a dominant-negative artifact versus a physiological role is not resolved
    • Substrates at the Golgi unknown
  5. 2003 Low

    Identification of PSKH1 as an in vitro Chk2 target raised the possibility of upstream phospho-regulation by DNA-damage signaling.

    Evidence GST-peptide in vitro kinase assay with consensus-site mutagenesis

    PMID:12711320

    Open questions at the time
    • No validation of in vivo phosphorylation by Chk2
    • Functional consequence unknown
  6. 2024 High

    Demonstrating that catalytically dead PSKH1 variants cause a hepatorenal ciliopathy established a definitive, kinase-activity-dependent physiological function in ciliogenesis.

    Evidence In vitro kinase assays of disease variants, patient fibroblast cilia imaging, and a homozygous Pskh1 mutant mouse

    PMID:39132680

    Open questions at the time
    • Ciliary substrate(s) of PSKH1 not identified
    • Molecular link between Golgi/ER localization and cilia phenotype unresolved
  7. 2025 High

    Defining the substrate motif and the allosteric regulators (Ca2+/CaM, UNC119B activating; Reticulocalbin-3 suppressing) provided the regulatory logic governing when PSKH1 is active.

    Evidence In vitro kinase assays, MS-based substrate motif profiling, and protein interaction biochemistry

    PMID:39964718

    Open questions at the time
    • In vivo substrates matching the motif not validated
    • Structural basis of non-canonical CaM activation not solved
    • Cellular context where each regulator dominates unclear
  8. 2023 Medium

    Placing PSKH1 upstream of p38/MAPK in osteosarcoma addressed how its catalytic role connects to growth control in cancer.

    Evidence shRNA/overexpression, proliferation/migration/invasion assays, SB203580 epistasis, and xenografts in OS cells

    PMID:36936027

    Open questions at the time
    • Direct mechanistic link between PSKH1 kinase activity and p38 activation not defined
    • Single tumor type

Open questions

Synthesis pass · forward-looking unresolved questions
  • The bona fide physiological substrates of PSKH1 and the mechanism connecting its membrane localization to cilia and splicing phenotypes remain unknown.
  • No validated in vivo substrate
  • No structural model of the active kinase or its regulatory complexes
  • Unclear how a Golgi/ER-anchored kinase controls ciliary length

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005654 nucleoplasm 2 GO:0005794 Golgi apparatus 2 GO:0005783 endoplasmic reticulum 1 GO:0005815 microtubule organizing center 1 GO:0005886 plasma membrane 1 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 1 R-HSA-1852241 Organelle biogenesis and maintenance 1 R-HSA-8953854 Metabolism of RNA 1
Partners
CALM1RCN3UNC119B

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PSKH1 protein autophosphorylates exclusively on serines within its C-terminal region in an intermolecular fashion; autophosphorylation activity is repressed upon addition of Ca2+/calmodulin, suggesting that PSKH1 activity is regulated by Ca2+ concentration in vivo. Immunoisolated PSKH1 does not phosphorylate common kinase substrates in vitro. In vitro kinase assay with immunoisolated PSKH1; Ca2+/CaM addition; mutational/biochemical analysis Genomics Medium 11087665
2000 PSKH1 localizes to the Golgi apparatus (Brefeldin A-sensitive compartment), centrosomes, and nucleus (speckle-like pattern) in COS-1 cells; centrosomal localization is enhanced during osmotic stress. Indirect immunofluorescence microscopy of untransfected COS-1 cells with polyclonal antibodies; Brefeldin A treatment Genomics Medium 11087665
2002 Endogenous PSKH1 localizes to splicing factor compartments (SFCs) in the nucleus; co-expression of SR proteins (ASF/SF2 and SC35) enhances PSKH1-FLAG migration into SFCs. PSKH1 overexpression reorganizes co-expressed SR proteins (SC35 and ASF/SF2) into a more diffuse nuclear pattern, and this redistribution does not require PSKH1 kinase activity. Forced PSKH1 expression stimulates distal splicing of an E1A minigene in HeLa cells. GST-ASF/SF2 is not phosphorylated by PSKH1, indicating indirect action on SR proteins. SFC-association maps to the catalytic kinase domain and C-terminus. Immunofluorescence microscopy; co-expression assays; E1A minigene splicing assay in HeLa cells; GST pulldown/kinase assay; yeast two-hybrid; domain truncation analysis Nucleic acids research Medium 12466556
2003 PSKH1 is myristoylated on glycine 2 and palmitoylated on cysteine 3. Dual acylation targets PSKH1 to the Golgi apparatus (co-localizing with beta-COP and GM130); myristoylation alone (without palmitoylation) redirects PSKH1 to ER membranes (co-localizing with PDI). The dually acylated N-terminal domain also targets plasma membrane. Expression of a PSKH1 mutant with the C-terminal kinase domain replaced by GFP and Cys3 mutated to Ser causes disassembly of the Golgi apparatus (redistribution of beta-COP and GM130 to diffuse cytoplasm) without affecting tubulin. The first 29 amino acids constitute the minimal Golgi-targeting region. Biochemical acylation assays; immunofluorescence co-localization with organelle markers (beta-COP, GM130, PDI); immunoelectron microscopy; subcellular fractionation by sucrose gradient; site-directed mutagenesis Experimental cell research High 14644153
2003 PSKH1 was identified as an in vitro substrate/target of Chk2 kinase using the GST-peptide approach based on defined phosphorylation consensus sequences. GST-peptide in vitro kinase assay; mutational analysis of consensus phosphorylation sites Biochemical and biophysical research communications Low 12711320
2020 Evolutionary analysis reveals that species-level duplications of the canonical PSKH1 kinase led to the appearance of the pseudokinase PSKH2, demonstrating that PSKH1 is a canonical active kinase in the CAMK family whose duplication gave rise to a catalytically inactive paralog. Comparative sequence analysis and kinome evolutionary analysis The FEBS journal Low 32053275
2024 Loss-of-function mutations in PSKH1 cause a novel hepatorenal ciliopathy. Recombinant PSKH1 disease variants show loss of catalytic activity in vitro. Patient fibroblasts display abnormally long cilia with aberrant transport. A homozygous Pskh1 mutant mouse recapitulates the human phenotype with abnormally long cilia, establishing that PSKH1 kinase activity is required for normal ciliogenesis and cilia-dependent transport. In vitro kinase assays of recombinant disease variants; immunofluorescence of patient fibroblast cilia; Pskh1 homozygous mutant mouse model with ciliary phenotype analysis Genetics in medicine High 39132680
2025 PSKH1's consensus substrate phosphorylation motif was defined biochemically. Ca2+-Calmodulin (CaM) activates PSKH1 despite the absence of a canonical CaM-binding motif, acting allosterically. Reticulocalbin-3 (an ER-resident Ca2+ sensor of the CREC family) suppresses PSKH1 catalytic activity via allosteric binding. UNC119B directly engages the PSKH1 kinase domain and activates PSKH1 catalytic activity. These represent complementary allosteric regulatory mechanisms that tune PSKH1 activity. Biochemistry (in vitro kinase assays); mass spectrometry-based substrate motif profiling; protein interaction studies (identification of interactors); domain-level binding/activity assays Proceedings of the National Academy of Sciences of the United States of America High 39964718
2023 PSKH1 knockdown in osteosarcoma cells inhibited proliferation, migration, and invasion, while PSKH1 overexpression promoted proliferation. PSKH1 upregulated phospho-p38 MAPK, and the p38 MAPK inhibitor SB203580 blocked the tumor-promoting effects of PSKH1, placing PSKH1 upstream of p38/MAPK signaling in osteosarcoma cells. shRNA knockdown and overexpression in OS cell lines; Cell Counting Kit-8, colony formation, wound-healing, Transwell assays; p38 inhibitor SB203580 treatment; in vivo tumor xenograft assay Oncology letters Medium 36936027
2012 shRNA knockdown of PSKH1 decreased cell growth in both androgen-dependent and castration-resistant prostate cancer cells (LNCaP), identifying PSKH1 as a regulator of prostate cancer cell growth. Lentiviral shRNA phenotypic screen; cell growth assays in LNCaP prostate cancer cells PloS one Low 22761715
2019 miR-566 directly targets PSKH1 mRNA (confirmed by luciferase reporter assay), suppressing PSKH1 protein expression; reintroduction of PSKH1 partially reversed the inhibitory effects of miR-566 on CRC cell growth and metastasis, placing PSKH1 downstream of miR-566 in colorectal cancer cell migration and invasion. Luciferase reporter assay; RT-PCR and western blot; miR-566 overexpression/inhibition; Transwell migration/invasion assays; PSKH1 rescue experiment Cancer cell international Medium 31866763

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 A tight cluster of five unrelated human genes on chromosome 16q22.1. Human molecular genetics 85 8268911
2000 Secondary structure prediction and in vitro accessibility of mRNA as tools in the selection of target sites for ribozymes. Nucleic acids research 57 11058107
2003 Determination of substrate specificity and putative substrates of Chk2 kinase. Biochemical and biophysical research communications 46 12711320
2012 Identification of kinases regulating prostate cancer cell growth using an RNAi phenotypic screen. PloS one 44 22761715
2020 Cataloguing the dead: breathing new life into pseudokinase research. The FEBS journal 39 32053275
2002 PSKH1, a novel splice factor compartment-associated serine kinase. Nucleic acids research 17 12466556
2000 Characterization of PSKH1, a novel human protein serine kinase with centrosomal, golgi, and nuclear localization. Genomics 17 11087665
2003 Mutants of the protein serine kinase PSKH1 disassemble the Golgi apparatus. Experimental cell research 16 14644153
2015 Exploratory biomarker analysis for treatment response in KRAS wild type metastatic colorectal cancer patients who received cetuximab plus irinotecan. BMC cancer 12 26486455
2024 Large-scale genomic investigation of pediatric cholestasis reveals a novel hepatorenal ciliopathy caused by PSKH1 mutations. Genetics in medicine : official journal of the American College of Medical Genetics 11 39132680
2019 MiR-566 mediates cell migration and invasion in colon cancer cells by direct targeting of PSKH1. Cancer cell international 11 31866763
2024 Regulation of myo-miR-24-3p on the Myogenesis and Fiber Type Transformation of Skeletal Muscle. Genes 7 38540328
2023 Evolutionary and cellular analysis of the 'dark' pseudokinase PSKH2. The Biochemical journal 4 36520605
2025 PSKH1 kinase activity is differentially modulated via allosteric binding of Ca2+ sensor proteins. Proceedings of the National Academy of Sciences of the United States of America 3 39964718
2023 PSKH1 affects proliferation and invasion of osteosarcoma cells via the p38/MAPK signaling pathway. Oncology letters 3 36936027
2019 Deep sequencing of a recurrent oligodendroglioma and the derived xenografts reveals new insights into the evolution of human oligodendroglioma and candidate driver genes. Oncotarget 3 31217899
2026 Living Donor Liver Transplantation for Progressive Familial Intrahepatic Cholestasis Type 13 (PFIC 13). Journal of clinical and experimental hepatology 0 42238902

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