Affinage

FAM20C

Extracellular serine/threonine protein kinase FAM20C · UniProt Q8IXL6

Length
584 aa
Mass
66.2 kDa
Annotated
2026-06-09
86 papers in source corpus 27 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAM20C is the Golgi-localized 'Golgi casein kinase', a serine/threonine kinase that phosphorylates secreted proteins at serine residues within the S-x-E/pSer motif and thereby acts as a master regulator of the secretory pathway across biomineralization, phosphate homeostasis, ER redox, lipid metabolism, coagulation, and cardiac calcium handling (PMID:22900076). It is a type II transmembrane protein anchored in the Golgi by its N-terminal region and is proteolytically processed by site-1 protease (S1P), with only the mature, S1P-processed form active in osteoblast differentiation and mineralization (PMID:34349020); its activity additionally depends allosterically on sphingosine, which supports Mg2+-dependent catalysis and protects the enzyme from inactivation (PMID:25936777). Through its kinase activity FAM20C governs a broad substrate repertoire: it phosphorylates FGF23 at Ser180 to block O-glycosylation and promote furin-mediated cleavage and inactivation, coupling it to phosphate-regulating hormone control (PMID:24706917); it phosphorylates osteopontin to weaken αvβ3 integrin binding and control its secretion, and BMP4 prodomain to enable proteolytic maturation, with opposing roles in osteoclastogenesis versus bone metastasis (PMID:32115754, PMID:34433585); and it modifies SIBLING/matrix substrates such as DMP1 and MEPE during bone mineralization (PMID:27614627, PMID:32803110). Beyond the matrix, FAM20C phosphorylates Ero1α (Ser145) to enhance ER oxidase activity and redox homeostasis (PMID:29858230), PCSK9 to maximize LDLR degradation (PMID:31553664), VWF in the A2 domain to enhance platelet adhesion under shear (PMID:30864273), Cab45 to control TGN cargo sorting (PMID:32422653), and HRC (Ser96) to regulate sarcoplasmic reticulum Ca2+ homeostasis and protect against arrhythmia (PMID:28784772). Raine syndrome mutations introduced into FAM20C impair its Golgi localization, secretion, and kinase activity (PMID:22900076, PMID:25026495), and disrupt its interaction with chondroitin 4-O-sulfotransferase-1, linking FAM20C to chondroitin sulfate composition and biomineralization (PMID:36572689). FAM20C activity also requires the pseudokinase FAM20A as a localization partner that directs FAM20C secretion and supports mineralization (PMID:27292199).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2012 High

    Established the core identity of FAM20C as the physiological Golgi casein kinase, defining its catalytic mechanism, substrate motif, and disease relevance in one founding study.

    Evidence In vitro kinase assays, kinetic and cation-dependence characterization, immunofluorescence localization, and mutagenesis of Raine syndrome variants

    PMID:22900076

    Open questions at the time
    • Did not resolve the full physiological substrate range
    • Mechanism of Golgi anchoring and processing not addressed
  2. 2013 Medium

    Resolved whether FAM20C functions intracellularly or in matrix by showing it is Golgi-restricted in tooth-forming cells and absent from enamel matrix.

    Evidence Immunohistochemistry of mouse incisors/molars and Western blot of pig enamel organ versus matrix

    PMID:23703840

    Open questions at the time
    • Negative enamel-matrix result is tissue-specific
    • Does not exclude extracellular activity in other tissues
  3. 2014 High

    Connected FAM20C to systemic phosphate homeostasis by demonstrating that FGF23 Ser180 phosphorylation gates its furin cleavage and inactivation, and that Raine mutants are catalytically deficient.

    Evidence In vitro kinase and furin cleavage assays, Ser180 mutagenesis, glycosylation analysis, and kinase-activity assays of multiple Raine variants

    PMID:24706917 PMID:25026495

    Open questions at the time
    • In vivo regulation of FGF23 cleavage by FAM20C in bone not fully resolved
    • Interplay with DMP1 expression only inferred from knockdown
  4. 2015 Medium

    Identified an allosteric activation mechanism, showing sphingosine confers Mg2+-supported activity and stabilizes the enzyme, explaining how FAM20C activity is tuned independently of protein level.

    Evidence In vitro kinase kinetics with sphingosine, thermal stability assays, and myriocin depletion in cells with conditioned-media activity readout

    PMID:25936777 PMID:28236661

    Open questions at the time
    • Physiological relevance of sphingolipid regulation in tissue not established
    • Binding site of sphingosine on FAM20C not mapped
  5. 2016 Medium

    Defined a localization partner and an in situ substrate, showing FAM20A directs FAM20C secretion/localization and that FAM20C co-localizes with DMP1 in the Golgi of bone cells before secretion.

    Evidence Co-transfection and conditioned-media analysis with Fam20a-null MEFs; immunoelectron microscopy of DMP1 phosphorylation in rat bone

    PMID:27292199 PMID:27614627

    Open questions at the time
    • FAM20A-FAM20C binding shown indirectly without direct pulldown
    • Structural basis of the FAM20A-FAM20C interaction unknown
  6. 2018 High

    Extended FAM20C beyond secreted matrix proteins into ER redox control by showing Ero1α Ser145 phosphorylation enhances oxidase activity, with retrograde transport coupling Golgi modification to ER function.

    Evidence Co-IP, phospho-site mapping, Ser145 mutagenesis, subcellular fractionation, and ER redox/oxidative folding assays

    PMID:29858230

    Open questions at the time
    • Stoichiometry and dynamics of Ero1α retrograde transport not fully quantified
    • Whether other ER-resident enzymes are similarly regulated unknown
  7. 2017 High

    Demonstrated a cardiac role by showing HRC Ser96 phosphorylation modulates triadin/SERCA2a interactions and rescues arrhythmogenic aftercontractions, placing FAM20C in SR Ca2+ homeostasis.

    Evidence In vitro kinase assay confirmed in human heart, phosphomimetic rescue in HRC-null cardiac myocytes, and Co-IP interaction studies

    PMID:28784772

    Open questions at the time
    • Source and trafficking of FAM20C to the SR lumen not defined
    • In vivo cardiac phenotype of FAM20C loss not directly tested here
  8. 2019 High

    Broadened the FAM20C substrate landscape into coagulation, lipid metabolism, fibrosis, and non-canonical motifs, showing phosphorylation of VWF, PCSK9, OPN, and phosvitin with distinct functional outcomes.

    Evidence In vitro kinase assays with MS site mapping, platelet adhesion under shear, hepatocyte LDLR degradation assays, HSC knockdown/secretion, and zebrafish/peptide phosphorylation with kinase-dead controls

    PMID:30387551 PMID:30864273 PMID:31553664 PMID:31914633

    Open questions at the time
    • In vivo contributions to thrombosis and cholesterol metabolism not established
    • Phosvitin polyserine targeting expands but does not fully define motif rules
  9. 2019 Medium

    Established the conserved developmental importance of the kinase by showing the C. elegans orthologue FAMK-1 is required for fertility, embryogenesis, and intercellular partition integrity via late-secretory-pathway activity.

    Evidence C. elegans RNAi/genetic analysis, tissue-specific rescue, and biochemical substrate identification implicating lectins

    PMID:31541016

    Open questions at the time
    • Lectin substrates not validated in mammals
    • Mechanistic link between substrate phosphorylation and partition maintenance unresolved
  10. 2020 Medium

    Refined how FAM20C controls secretion and matrix protein function, showing it tunes Cab45 oligomerization for TGN cargo sorting, weakens OPN-integrin binding, and binds Periostin in a kinase-independent manner.

    Evidence In vitro kinase and phosphomimetic assays, vesicle fractionation and client secretion (Cab45/LyzC), integrin-binding assays (OPN), and binding/domain mapping with co-localization (Periostin)

    PMID:32115754 PMID:32422653 PMID:33051588

    Open questions at the time
    • Kinase-independent Periostin binding role not functionally defined
    • How phosphorylation regulates Cab45 oligomeric state structurally unknown
  11. 2021 High

    Dissected the architecture and processing of FAM20C and its opposing roles in bone, showing S1P-dependent maturation activates it, and that it suppresses osteoclastogenesis via OPN but promotes bone metastasis via BMP4 secretion.

    Evidence Domain mutagenesis and S1P co-expression with osteoblast assays; myeloid-specific and tumor cell Fam20C manipulation with phosphoproteomics, site mutagenesis, and in vivo metastasis models

    PMID:34349020 PMID:34433585

    Open questions at the time
    • Trigger and regulation of S1P processing in vivo not defined
    • Context-dependent OPN vs BMP4 substrate selection mechanism unclear
  12. 2022 Medium

    Linked Raine-causing mutations to glycosaminoglycan composition, showing loss of FAM20C-C4ST-1 interaction shifts chondroitin sulfate sulfation and dysregulates biomineralization.

    Evidence Co-IP of FAM20C with C4ST-1 and Raine variants, MS sulfation analysis, and C6ST-1 overexpression in cells and transgenic mice

    PMID:36572689

    Open questions at the time
    • Whether C4ST-1 is a phosphorylation substrate or only a binding partner unclear
    • Kinase-dependence of the sulfation effect not separated
  13. 2023 Medium

    Connected FAM20C to cytoskeletal and Wnt regulation in bone by identifying Calpastatin as a substrate whose phosphorylation modulates the Calpain axis, migration, and F-actin.

    Evidence Integrated ATAC-seq, RNA-seq, proteomics, and phosphoproteomics in Fam20c-deficient osteoblasts

    PMID:37370126

    Open questions at the time
    • Direct in vitro Calpastatin phosphorylation not reconstituted
    • Causal chain to Wnt signaling correlative
  14. 2025 Medium

    Expanded FAM20C into metabolic disease and additional substrates, implicating it in adipocyte insulin resistance via CNPY4, and characterizing a Golgi-mislocalizing insertion variant that retains dimerization.

    Evidence Adipocyte-specific Fam20c KO/gain-of-function with kinase-dead controls and CNPY4 phosphoproteomics; exome/cDNA sequencing with localization, secretion, and dimerization Co-IP for the insertion variant

    PMID:40794899 PMID:41148235

    Open questions at the time
    • CNPY4 phosphorylation site and direct catalysis not fully mapped
    • Functional consequence of dimerization remains undefined
  15. 2025 Low

    Proposed novel intracellular and hormone-linked roles, implicating FAM20C in CNS neuronal differentiation via KAP1 and in aldosterone-driven FGF23 cleavage.

    Evidence FAM20C knockdown/overexpression in neural cells with chromatin/m6A assays and a HIBD model; FAM20C siRNA with cFGF23 readout and aldosterone docking

    PMID:39989455 PMID:40511628

    Open questions at the time
    • Direct FAM20C-KAP1 phosphorylation not reconstituted in vitro
    • Aldosterone-FAM20C binding only computational, not biochemically confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FAM20C substrate selection and activity are spatially and contextually controlled across the diverse organ systems it regulates remains unresolved.
  • No structural model explaining substrate motif breadth (canonical S-x-E vs polyserine)
  • Tissue-specific regulators of S1P processing and sphingosine activation not identified
  • Unified rules governing opposing physiological outcomes (e.g. OPN vs BMP4) absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016740 transferase activity 5 GO:0140657 ATP-dependent activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005794 Golgi apparatus 6 GO:0005576 extracellular region 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1474244 Extracellular matrix organization 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-9609507 Protein localization 2 R-HSA-109582 Hemostasis 1 R-HSA-8953897 Cellular responses to stimuli 1
Partners
CAB45CHST11ERO1AFAM20AFGF23HRCPCSK9POSTN

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 FAM20C is a Golgi-localized protein kinase (the Golgi casein kinase) that phosphorylates secreted phosphoproteins including casein and SIBLING family members at serine residues specified by the S-x-E/pSer motif. Autophosphorylation was also identified. Raine syndrome patient mutations introduced into recombinant FAM20C impaired its normal Golgi localization and kinase activity. In vitro kinase assay, Km/pH/cation-dependence characterization, subcellular localization by immunofluorescence, site-directed mutagenesis of patient variants PloS one High 22900076
2014 FAM20C directly phosphorylates FGF23 on Ser180 within the R176XXR179/S180AE furin cleavage motif. This phosphorylation inhibits O-glycosylation by GalNAc-T3 and promotes FGF23 cleavage and inactivation by the proprotein convertase furin, providing a molecular mechanism for dynamic regulation of the phosphate-regulating hormone FGF23. In vitro kinase assay with recombinant FAM20C and FGF23, site-directed mutagenesis of Ser180, co-expression studies in cells, furin cleavage assays, glycosylation analysis Proceedings of the National Academy of Sciences of the United States of America High 24706917
2017 FAM20C phosphorylates histidine-rich calcium-binding protein (HRC) on Ser96 within the sarcoplasmic reticulum (SR) lumen. This phosphorylation regulates HRC interactions with triadin and SERCA2a; a phosphomimetic Ser96Asp variant rescued delayed aftercontractions in HRC-null cardiac myocytes, establishing that Fam20C-dependent HRC phosphorylation is critical for SR Ca2+ homeostasis and cardioprotection against arrhythmia. In vitro kinase assay, phosphorylation confirmed in cells and human hearts, phosphomimetic and phospho-null HRC variants in cardiac myocyte functional assays, Co-IP for HRC-triadin and HRC-SERCA2a interactions Proceedings of the National Academy of Sciences of the United States of America High 28784772
2018 FAM20C phosphorylates Ero1α (ER oxidoreductin 1α) on Ser145 in the Golgi apparatus; phosphorylated Ero1α is then retrograde-transported to the ER mediated by ERp44. Ser145 phosphorylation greatly enhances Ero1α oxidase activity and is critical for ER redox homeostasis and oxidative protein folding. Phosphorylation is induced under hypoxia, reductive stress, and lactation. Co-IP, phospho-site mapping, in vitro kinase assay, mutagenesis of Ser145, subcellular fractionation, ER redox measurements, functional oxidative folding assays The EMBO journal High 29858230
2019 FAM20C phosphorylates PCSK9 at Ser47, Ser666, Ser668, and Ser688. In hepatocytes, phosphorylation enhances PCSK9 secretion and maximizes its induced degradation of the LDLR via both extracellular and intracellular pathways. Phosphomimetic (Glu/Asp) substitutions enhanced PCSK9 activity only when other sites were also phosphorylated; Ala substitutions reduced LDLR degradation. Mass spectrometry phospho-site identification, phosphomimetic and phospho-null mutagenesis, Western blot, ELISA, LDLR immunolabeling in hepatocytes Arteriosclerosis, thrombosis, and vascular biology High 31553664
2021 FAM20C exists as a type II transmembrane protein within secretory compartments, with its N-terminal signal peptide-like region serving as a membrane anchor for Golgi retention. Site-1 protease (S1P) proteolytically processes FAM20C, and only the mature, S1P-processed form of FAM20C is active in osteoblast differentiation and mineralization. Subcellular fractionation, domain deletion/mutagenesis, co-expression with S1P in cells, functional osteoblast differentiation and mineralization assays Proceedings of the National Academy of Sciences of the United States of America High 34349020
2020 FAM20C phosphorylates Ser146 in the RGDSVVYGLR motif of osteopontin (OPN). This phosphorylation significantly reduces RGD-mediated interaction of OPN with the αvβ3 integrin, but does not affect thrombin or plasmin cleavage susceptibility. Ser146 phosphorylation was confirmed in vivo in human and bovine milk. In vitro kinase assay, phospho-specific peptide synthesis, cell-based integrin-binding assay (MDA-MB-435 and Moαv cells), proteolytic cleavage assays, in vivo phosphorylation confirmed by mass spectrometry of milk samples Journal of cellular biochemistry High 32115754
2019 FAM20C phosphorylates the VWF A2 domain at Ser1517 and Ser1613 in vitro. Phosphorylation at Ser1613 (the major site) enhances stable platelet adhesion and microthrombus formation under high shear stress, establishing FAM20C-dependent phosphorylation as a novel post-translational modification that enhances VWF adhesiveness. In vitro kinase assay with purified plasma VWF and isolated A2 domain, mass spectrometry phospho-site identification, platelet adhesion assays under high shear stress, plasma VWF phosphorylation confirmed by MS Journal of thrombosis and haemostasis : JTH High 30864273
2020 FAM20C phosphorylates the cargo-sorting protein Cab45 in the TGN. Phosphomimetic Cab45 translocates into TGN-derived vesicles and increases export of the Cab45 client LyzC, demonstrating that FAM20C fine-tunes Cab45 oligomerization and thereby controls sorting/secretion of Cab45 clients. In vitro kinase assay, phosphomimetic mutagenesis, vesicle fractionation, client protein secretion assay (LyzC), quantitative proteomics The Journal of cell biology High 32422653
2021 FAM20C in myeloid cells suppresses osteoclastogenesis and bone resorption via phosphorylation of osteopontin (OPN); OPN phosphorylation by FAM20C decreased OPN secretion, and OPN neutralization reduced FAM20C-deficiency-induced osteoclast differentiation. In contrast, FAM20C in breast cancer cells promoted bone metastasis by phosphorylating and facilitating secretion of BMP4; mutation of the BMP4 FAM20C phosphorylation site elevated BMP4 lysosomal degradation and reduced BMP4 secretion. Conditional knockout mice (myeloid-specific Fam20C KO), phosphoproteomic identification of OPN as most abundant Fam20C-dependent phosphoprotein, OPN neutralization experiments, BMP4 phosphorylation site mutagenesis, lysosomal degradation assays, in vivo bone metastasis models Cancer research High 34433585
2019 FAM20C phosphorylation of OPN is essential for OPN secretion from hepatic stellate cells (HSCs). In HSCs activated during liver fibrogenesis, FAM20C becomes overactive when associated with a ~500-kDa multiprotein complex. However, OPN promotes fibrosis (collagen-I expression) independently of its phosphorylation state. Bile duct ligation mouse model, HSC culture, Fam20C knockdown, OPN phosphorylation and secretion measurement, gel filtration to identify Fam20C complex, recombinant phosphorylated vs. unphosphorylated OPN functional assays FASEB journal Medium 31914633
2016 FAM20A binds to FAM20C and controls FAM20C localization; wild-type FAM20A co-transfection increases extracellular FAM20C localization, whereas AI-form FAM20A mutants do not. In Fam20a knockout MEFs, FAM20C is absent from conditioned media, and media from FAM20A-null MEFs fail to support mineralization in vitro. Co-transfection, conditioned media analysis, Fam20a knockout MEF experiments, in vitro mineralization assay Scientific reports Medium 27292199
2020 FAM20C directly binds to and phosphorylates Periostin in vitro. The interaction is kinase-activity independent and maps to the Fasciclin I domain 1-4 of Periostin. FAM20C and Periostin co-localize in periodontal ligament ECM in vivo. Mass spectrometry identification of FAM20C-binding proteins, in vitro binding assay with recombinant proteins, domain mapping, in vitro kinase assay, immunohistochemistry co-localization in mouse periodontium Scientific reports Medium 33051588
2015 Sphingosine activates FAM20C kinase activity in vitro, conferring Mg2+-supported activity (normally requiring high Mn2+) and increasing Vmax while decreasing Km(ATP). Sphingosine also protects FAM20C from thermal inactivation. Depletion of endogenous sphingosine with myriocin in FAM20C-expressing HEK293T cells substantially decreases FAM20C activity in conditioned media. In vitro kinase assay with sphingosine, kinetic analysis (Vmax, KmATP), thermal stability assay, myriocin treatment of cells with conditioned media activity measurement Biochimica et biophysica acta Medium 25936777
2017 Sphingolipid signaling controls FAM20C kinase activity in human cell lines: myriocin-mediated depletion of endogenous sphingosine reduces FAM20C activity in both cell lysates and conditioned media to negligible levels; this can be partially restored by exogenous sphingosine or ceramide. FAM20C activity changes are not accompanied by changes in FAM20C protein levels, consistent with an allosteric/cofactor mechanism. CRISPR/Cas9 FAM20C knockout cells as negative control, kinase activity assays in wild-type vs. KO cells, myriocin/sphingosine treatment, sphingosine analog panel The FEBS journal Medium 28236661
2018 FAM20C (Golgi casein kinase) is the kinase responsible for phosvitin phosphorylation. It phosphorylates polyserine stretches lacking the canonical S-x-E motif, expanding the known FAM20C substrate repertoire. Evidence includes parallel upregulation of Fam20C and phospho-vitellogenin in zebrafish upon estrogen treatment, phosphorylation of zebrafish phosvitin by co-expressed FAM20C (but not catalytically inactive mutant) in U2OS cells, and direct phosphorylation of a 12-serine peptide by recombinant and native Fam20C. Zebrafish estrogen treatment with phospho-VTG and Fam20C co-expression assay, in vitro kinase assay with synthetic peptides, kinase-dead mutant controls The FEBS journal Medium 30387551
2013 FAM20C localizes intracellularly within ameloblasts and odontoblasts in a pattern consistent with Golgi localization, and is NOT detectable in the enamel extracellular matrix. Western blot detected FAM20C in enamel organ epithelia but not enamel matrix, arguing against an extracellular kinase function in enamel. Immunohistochemistry in day-5 mouse incisors/molars, Western blot of pig enamel organ epithelia and enamel shavings Journal of bone and mineral research Medium 23703840
2016 FAM20C co-localizes with its substrate C-terminal DMP1 in the Golgi of osteoblastic, osteoid, and young osteocytes in rat bone. Phosphorylated C-terminal DMP1 was detected in the Golgi of young osteocytes and subsequently localized to the pericanalicular wall in mineralized bone by double-labeling immunoelectron microscopy, supporting a model in which FAM20C phosphorylates DMP1 intracellularly before secretion. Immunohistochemistry, immunofluorescence co-localization, double-labeling immunoelectron microscopy in rat bone sections Histochemistry and cell biology Medium 27614627
2014 All six Raine syndrome FAM20C mutant proteins (T268M, P328S, R408W, D451N, D478A, R549W) showed decreased kinase activities compared to wild-type FAM20C, and most also showed impaired secretion. Fam20c knockdown in UMR-106 cells decreased Dmp1 mRNA and increased Fgf23 mRNA, suggesting FAM20C suppresses FGF23 by enhancing DMP1 expression. In vitro kinase activity assays for each mutant, cellular localization/secretion analysis, DMP1 promoter-reporter assay, shRNA knockdown in osteogenic cells with qPCR Bone Medium 25026495
2022 FAM20C with Raine syndrome mutations loses the ability to interact with chondroitin 4-O-sulfotransferase-1 (C4ST-1), and this is associated with a reduced 4S/6S ratio of chondroitin sulfate (CS) chains and upregulated biomineralization in human osteosarcoma cells. Overexpressing chondroitin 6-O-sulfotransferase-1 (C6ST-1) to reduce CS 4S/6S ratio induced osteoblast differentiation in vitro and higher bone mineral density in transgenic mice. Co-IP of FAM20C with C4ST-1, Raine mutation variants tested for interaction loss, CS sulfation analysis by mass spectrometry, C6ST-1 overexpression in cells and transgenic mice Nature communications Medium 36572689
2021 FAM20C phosphorylates all serine residues in the canonical S-x-E target sequence of MEPE (matrix extracellular phosphoglycoprotein), with 31 phosphoresidues identified after co-expression with FAM20C in HEK293T cells. All nine serine residues in the ASARM motif were phosphorylated, even those not in the canonical motif. Co-expression of MEPE with FAM20C in HEK293T cells, mass spectrometry-based phospho-site mapping JBMR plus Medium 32803110
2019 FAMK-1, the C. elegans FAM20C orthologue, is required for fertility, embryogenesis, and development in C. elegans. Its functions require activity in the late (not early) secretory pathway. During embryogenesis, FAMK-1 maintains intercellular partitions and prevents multinucleation. Biochemical and functional analysis implicated lectins as FAMK-1 substrates. C. elegans RNAi and genetic analysis, tissue-specific expression rescue experiments, temperature and cortical stiffness perturbation, informatic and biochemical substrate identification The Journal of cell biology Medium 31541016
2023 FAM20C phosphorylates Calpastatin, a regulator of the Calpain proteolysis system. Loss of Fam20c in osteoblasts leads to dysregulation of the Calpastatin/Calpain axis, affecting cell migration and F-actin cytoskeleton. The Calpastatin/Calpain system in turn negatively regulates the Wnt signaling pathway. ATAC-seq, RNA-seq, proteomics, and phosphoproteomics in Fam20c-deficient osteoblasts; pathway analysis identifying Calpastatin as phosphorylation target Journal of translational medicine Medium 37370126
2025 FAM20C phosphorylates KAP1 (KRAB-associated protein 1) in the CNS. In hypoxic-ischemic brain damage (HIBD), suppressed FAM20C reduces KAP1 phosphorylation, which affects the YTHDC1-NCL-KAP1-LINE1 RNA complex and LINE1 RNA m6A levels, consequently altering H3K9me3 modification on LINE1 DNA and impairing neuronal differentiation. FAM20C knockdown/overexpression in neural cells, KAP1 identified as kinase substrate, m6A and H3K9me3 chromatin assays, co-IP of YTHDC1-NCL-KAP1 complex, HIBD mouse model Cell proliferation Low 40511628
2025 FAM20C promotes insulin resistance and inflammation in adipocytes in an obesity context. Its kinase activity is required for proinflammatory cytokine upregulation. Phosphoproteomic analysis identified CNPY4 as a FAM20C-dependent substrate whose phosphorylation contributes to proinflammatory adipocyte signaling. Adipocyte-specific deletion of Fam20c improved glucose tolerance and insulin sensitivity after established obesity. Adipocyte-specific Fam20c KO mice, forced Fam20c expression in adipocytes, kinase-dead mutant controls, phosphoproteomics in adipocytes, CNPY4 substrate identification The Journal of clinical investigation Medium 41148235
2025 FAM20C (or its product) can form homo- and hetero-dimers. A 12-amino-acid insertion variant caused by a splice-site mutation failed to localize properly to the Golgi apparatus and exhibited poor secretion from cells, establishing that correct Golgi localization and secretion depend on proper protein structure in this region, while dimerization was unaffected. Exome sequencing, mRNA/cDNA sequencing to identify in-frame insertion, co-immunoprecipitation for homo/heterodimer analysis, subcellular localization by immunofluorescence, secretion assay by conditioned media Western blot Human molecular genetics Medium 40794899
2025 Aldosterone enhances cleavage of intact FGF23 (iFGF23) to C-terminal FGF23 (cFGF23) via FAM20C; silencing FAM20C in cell cultures mitigated aldosterone-induced increases in cFGF23 levels. Docking experiments indicate aldosterone binds to FAM20C. The furin inhibitor did not affect the aldosterone-enhanced cFGF23 levels. FAM20C siRNA knockdown in cell culture, measurement of cFGF23 and iFGF23, molecular docking of aldosterone to FAM20C structure JCI insight Low 39989455
2024 Mutations that disrupt the conserved FAM20C phosphorylation motif in the BMP4 prodomain (S91C and E93G) prevent proteolytic activation of BMP4 homodimers (but not BMP4/7 heterodimers), leading to accumulation of BMP4 precursor, reduced cleaved BMP4 ligand, and reduced BMP activity in vivo. This establishes that FAM20C-mediated phosphorylation of the BMP4 prodomain is required for proper proteolytic maturation of BMP4 homodimers. Xenopus embryo functional assays comparing wild-type and mutant BMP4, knock-in mice (Bmp4 S91C and E93G), MEF cultures showing precursor accumulation and reduced cleaved ligand by Western blot, BMP activity reporter assays bioRxivpreprint Medium

Source papers

Stage 0 corpus · 86 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proceedings of the National Academy of Sciences of the United States of America 252 24706917
2007 Mutations in FAM20C are associated with lethal osteosclerotic bone dysplasia (Raine syndrome), highlighting a crucial molecule in bone development. American journal of human genetics 171 17924334
2012 Inactivation of a novel FGF23 regulator, FAM20C, leads to hypophosphatemic rickets in mice. PLoS genetics 151 22615579
2012 The Raine syndrome protein FAM20C is a Golgi kinase that phosphorylates bio-mineralization proteins. PloS one 140 22900076
2012 Amelogenesis imperfecta and other biomineralization defects in Fam20a and Fam20c null mice. Veterinary pathology 110 22732358
2009 Mutations in FAM20C also identified in non-lethal osteosclerotic bone dysplasia. Clinical genetics 97 19250384
2015 Variability of systemic and oro-dental phenotype in two families with non-lethal Raine syndrome with FAM20C mutations. BMC medical genetics 65 25928877
2010 Osteosclerotic bone dysplasia in siblings with a Fam20C mutation. Clinical genetics 63 20825432
2012 FAM20C plays an essential role in the formation of murine teeth. The Journal of biological chemistry 62 22936805
2010 Expression of FAM20C in the osteogenesis and odontogenesis of mouse. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 62 20644212
2014 Hypophosphatemic osteomalacia and bone sclerosis caused by a novel homozygous mutation of the FAM20C gene in an elderly man with a mild variant of Raine syndrome. Bone 58 24982027
2018 Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α. The EMBO journal 52 29858230
2019 Ser-Phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (Family With Sequence Similarity 20, Member C) Kinase Enhances Its Ability to Degrade the LDLR (Low-Density Lipoprotein Receptor). Arteriosclerosis, thrombosis, and vascular biology 45 31553664
2021 Fam20C Regulates Bone Resorption and Breast Cancer Bone Metastasis through Osteopontin and BMP4. Cancer research 40 34433585
2016 FAM20A binds to and regulates FAM20C localization. Scientific reports 38 27292199
2016 Raine Syndrome (OMIM #259775), Caused By FAM20C Mutation, Is Congenital Sclerosing Osteomalacia With Cerebral Calcification (OMIM 259660). Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 38 27862258
2017 FAM20C could be targeted by TET1 to promote odontoblastic differentiation potential of human dental pulp cells. Cell proliferation 34 29277934
2013 Hereditary deletion of the entire FAM20C gene in a patient with Raine syndrome. American journal of medical genetics. Part A 34 24039075
2020 Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C. Neuro-oncology 32 32386320
2017 Phosphorylation of serine96 of histidine-rich calcium-binding protein by the Fam20C kinase functions to prevent cardiac arrhythmia. Proceedings of the National Academy of Sciences of the United States of America 31 28784772
2013 The specific role of FAM20C in amelogenesis. Journal of dental research 31 24026952
2021 Proteolytic processing of secretory pathway kinase Fam20C by site-1 protease promotes biomineralization. Proceedings of the National Academy of Sciences of the United States of America 29 34349020
2020 Discovery of a novel small-molecule inhibitor of Fam20C that induces apoptosis and inhibits migration in triple negative breast cancer. European journal of medicinal chemistry 29 33316691
2014 Functional analysis of mutant FAM20C in Raine syndrome with FGF23-related hypophosphatemia. Bone 28 25026495
2017 FAM20C regulates osteoblast behaviors and intracellular signaling pathways in a cell-autonomous manner. Journal of cellular physiology 27 28926103
2021 FAM20C Overview: Classic and Novel Targets, Pathogenic Variants and Raine Syndrome Phenotypes. International journal of molecular sciences 26 34360805
2018 A novel FAM20C mutation causing hypophosphatemic osteomalacia with osteosclerosis (mild Raine syndrome) in an elderly man with spontaneous osteonecrosis of the knee. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 24 30151622
2017 Specific ablation of mouse Fam20C in cells expressing type I collagen leads to skeletal defects and hypophosphatemia. Scientific reports 24 28620244
2016 Immunohistochemical analysis of dentin matrix protein 1 (Dmp1) phosphorylation by Fam20C in bone: implications for the induction of biomineralization. Histochemistry and cell biology 20 27614627
2014 Inactivation of Fam20C in cells expressing type I collagen causes periodontal disease in mice. PloS one 20 25479552
2013 FAM20C functions intracellularly within both ameloblasts and odontoblasts in vivo. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20 23703840
2019 Non-lethal Raine Syndrome in a Middle-Aged Woman Caused by a Novel FAM20C Mutation. Calcified tissue international 19 31471673
2021 Fam20C in Human Diseases: Emerging Biological Functions and Therapeutic Implications. Frontiers in molecular biosciences 18 34988120
2020 Fam20C regulates protein secretion by Cab45 phosphorylation. The Journal of cell biology 18 32422653
2019 A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome. American journal of medical genetics. Part A 18 31297960
2016 Systematic network-based discovery of a Fam20C inhibitor (FL-1607) with apoptosis modulation in triple-negative breast cancer. Molecular bioSystems 18 27113542
2015 A new role for sphingosine: Up-regulation of Fam20C, the genuine casein kinase that phosphorylates secreted proteins. Biochimica et biophysica acta 16 25936777
2020 FAM20C phosphorylation of the RGDSVVYGLR motif in osteopontin inhibits interaction with the αvβ3 integrin. Journal of cellular biochemistry 15 32115754
2019 In vitro phosphorylation of von Willebrand factor by FAM20c enhances its ability to support platelet adhesion. Journal of thrombosis and haemostasis : JTH 15 30864273
2019 Loss of Fam20c causes defects in the acinar and duct structure of salivary glands in mice. International journal of molecular medicine 15 30864688
2018 Abrogation of Fam20c altered cell behaviors and BMP signaling of immortalized dental mesenchymal cells. Experimental cell research 15 29337188
2018 The Golgi 'casein kinase' Fam20C is a genuine 'phosvitin kinase' and phosphorylates polyserine stretches devoid of the canonical consensus. The FEBS journal 15 30387551
2020 Two Novel FAM20C Variants in A Family with Raine Syndrome. Genes 14 32093234
2020 FAM20C directly binds to and phosphorylates Periostin. Scientific reports 14 33051588
2020 Ablation of Fam20c causes amelogenesis imperfecta via inhibiting Smad dependent BMP signaling pathway. Biology direct 13 33028367
2017 Fam20C is under the control of sphingolipid signaling in human cell lines. The FEBS journal 13 28236661
2015 Characterization of Fam20C expression in odontogenesis and osteogenesis using transgenic mice. International journal of oral science 12 25537657
2014 Overexpression of Dmp1 fails to rescue the bone and dentin defects in Fam20C knockout mice. Connective tissue research 12 24874551
2015 Immortalized Mouse Floxed Fam20c Dental Papillar Mesenchymal and Osteoblast Cell Lines Retain Their Primary Characteristics. Journal of cellular physiology 11 25833681
2023 Epigenetic and transcriptional activation of the secretory kinase FAM20C as an oncogene in glioma. Journal of genetics and genomics = Yi chuan xue bao 10 36708808
2022 Altered sulfation status of FAM20C-dependent chondroitin sulfate is associated with osteosclerotic bone dysplasia. Nature communications 9 36572689
2019 Ancestral roles of the Fam20C family of secreted protein kinases revealed in C. elegans. The Journal of cell biology 9 31541016
2018 fam20C participates in the shell formation in the pearl oyster, Pinctada fucata. Scientific reports 9 29476076
2023 Fam20c regulates the calpain proteolysis system through phosphorylating Calpasatatin to maintain cell homeostasis. Journal of translational medicine 8 37370126
2020 High-Phosphate Diet Improved the Skeletal Development of Fam20c-Deficient Mice. Cells, tissues, organs 8 32101876
2019 Fam20C-mediated phosphorylation of osteopontin is critical for its secretion but dispensable for its action as a cytokine in the activation of hepatic stellate cells in liver fibrogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 31914633
2021 Recurrent variant c.1680C>A in FAM20C gene and genotype-phenotype correlation in a patient with Raine syndrome: a case report. BMC pediatrics 7 33676444
2020 FAM20C-Mediated Phosphorylation of MEPE and Its Acidic Serine- and Aspartate-Rich Motif. JBMR plus 7 32803110
2021 FAM20C plays a critical role in the development of mouse vertebra. The spine journal : official journal of the North American Spine Society 6 34343663
2022 Ablation of FAM20C caused short root defects via suppressing the BMP signaling pathway in mice. Journal of orofacial orthopedics = Fortschritte der Kieferorthopadie : Organ/official journal Deutsche Gesellschaft fur Kieferorthopadie 5 35316352
2021 From biomineralization to tumorogenesis-the expanding insight of the physiological and pathological roles of Fam20C. Bioscience reports 5 33942849
2023 Potential Role of Protein Kinase FAM20C on the Brain in Raine Syndrome, an In Silico Analysis. International journal of molecular sciences 4 37240249
2023 FAM20C: A key protein kinase in multiple diseases. Genes & diseases 4 39790934
2022 Mesenchymal-to-epithelial transition of osteoblasts induced by Fam20c knockout. Genes & genomics 4 35025083
2021 Nonlethal Raine Syndrome in a Newborn Boy Caused by a Novel FAM20C Variant. Molecular syndromology 4 34177433
2024 Knocking out FAM20C in pre-osteoblasts leads to up-regulation of osteoclast differentiation to affect long bone development. Gene 3 38552750
2024 Discovery of a novel Fam20C inhibitor for treatment of triple-negative breast cancer. International journal of biological macromolecules 3 39647747
2023 Intracranial calcification in Fam20c-deficient mice recapitulates human Raine syndrome. Neuroscience letters 3 36914045
2021 Molecular Cloning of Mouse Homologue of Enamel Protein C4orf26 and Its Phosphorylation by FAM20C. Calcified tissue international 3 33884476
2021 In situ determination of secretory kinase Fam20C from living cells using fluorescence correlation spectroscopy. Talanta 3 34074441
2025 Mutant Fam20c knock-in mice recapitulate both lethal and non-lethal human Raine Syndrome. BMC molecular and cell biology 2 39748245
2025 FAM20C Modulates Neuronal Differentiation in Hypoxic-Ischemic Brain Damage via KAP1 Phosphorylation and LINE1 RNA m6A-Dependent H3K9me3 Regulation. Cell proliferation 2 40511628
2025 Protein kinase FAM20C-when subcellular localization matters. FEBS letters 2 40970502
2024 Raine syndrome: Prenatally identified severe craniofacial phenotype with multisuture synostosis and brain abnormalities associated with variants in FAM20C. Prenatal diagnosis 2 38163266
2024 FAM20C Promotes Papillary Thyroid Cancer Proliferation and Metastasis via Epithelial-Mesenchymal Transition. Molecular carcinogenesis 2 39436102
2023 Emerging mechanisms of regulation for endoplasmic/sarcoplasmic reticulum Ca2+ stores by secretory pathway kinase FAM20C. Current opinion in chemical biology 2 36966700
2021 Effect of high phosphate diet on the formation of dentin in Fam20c-deficient mice. European journal of oral sciences 2 33905141
2020 Ras-transformation reduce FAM20C expression and osteopontin phosphorylation. Bioscience reports 2 32830861
2025 C-terminal FGF-23 production coupling with aldosterone via FAM20C and predicting cardiovascular events in primary aldosteronism. JCI insight 1 39989455
2025 Enhancer hijacking drives FAM20C expression to promote papillary thyroid cancer progression. Cancer gene therapy 1 40588505
2025 A synonymous single nucleotide variant on the FAM20C gene causes non-lethal Raine syndrome. Human molecular genetics 1 40794899
2025 Secretory kinase FAM20C triggers adipocyte dysfunction, inciting insulin resistance and inflammation in obesity. The Journal of clinical investigation 1 41148235
2025 Comprehensive Analysis of the Putative Substratome of FAM20C, the Master Serine Kinase of the Secretory Pathway. Biomolecules 1 41301500
2023 Compound heterozygous FAM20C gene variants in a patient with severe Raine syndrome: a case report. Frontiers in genetics 1 37180977
2026 Novel compound heterozygous FAM20C variants cause Raine syndrome - retrospective prenatal diagnosis and literature review. Orphanet journal of rare diseases 0 41896969
2025 An Uncommon Case of Hypophosphataemia-Non-Lethal Raine Syndrome With Novel FAM20C Variant: Expanding the Phenotypic Spectrum. American journal of medical genetics. Part A 0 41174912

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