Affinage

ALPL

Alkaline phosphatase, tissue-nonspecific isozyme · UniProt P05186

Length
524 aa
Mass
57.3 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALPL encodes tissue-nonspecific alkaline phosphatase (TNAP), a GPI-anchored ectoenzyme with broad phosphohydrolase activity that serves as a master regulator of biomineralization, purinergic signaling, and energy metabolism across multiple tissues. In the skeletal and dental compartments, TNAP is the principal enzyme hydrolyzing inorganic pyrophosphate (PPi), ATP, and related substrates in matrix vesicles to control hydroxyapatite deposition, cooperating non-redundantly with PHOSPHO1 and counterbalanced by NPP1-generated PPi (PMID:19874193, PMID:26457330, PMID:25504209); loss-of-function mutations cause hypophosphatasia, and specific missense variants exert dominant-negative effects on the wild-type homodimer (PMID:24022022). Beyond mineralization, TNAP localizes to mitochondria of thermogenic adipocytes where it functions as a phosphocreatine phosphatase driving a futile creatine cycle downstream of α1-adrenergic/Gαq signaling, and its adipocyte-specific ablation causes obesity (PMID:33981039, PMID:36344764); in non-skeletal tissues TNAP directly dephosphorylates SMAD2/3 to attenuate TGF-β signaling and fibrosis (PMID:31289197), regulates extracellular ATP and purinergic tone in the CNS (PMID:29551976), and when overexpressed in the vasculature drives arterial calcification through PPi depletion and osteogenic reprogramming (PMID:26675253, PMID:27932058). TNAP catalytic competence requires zinc loading via ZnT1/metallothionein/ZnT4 in the early secretory pathway, and its activity is further modulated by the lipid composition of the membrane in which its GPI anchor resides (PMID:24204829, PMID:32710882).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2010 High

    Establishing TNAP as the dominant phosphohydrolase in matrix vesicles resolved which enzyme primarily cleaves PPi and ATP to initiate skeletal mineralization.

    Evidence Kinetic analysis of substrate hydrolysis by wild-type vs. TNAP-, NPP1-, and PHOSPHO1-deficient osteoblast matrix vesicles

    PMID:19874193

    Open questions at the time
    • Relative contributions of each enzyme at different stages of MV maturation not resolved
    • No structural basis for substrate preference
  2. 2011 High

    Identification of the Dhx36–HDAC1/4 axis as a transcriptional regulatory mechanism for ALPL revealed how epigenetic signals control TNAP expression during osteogenesis.

    Evidence Promoter deletion constructs, DNA affinity precipitation, co-IP of Dhx36 with HDACs, and in vivo bone regeneration after HDAC inhibitor treatment

    PMID:21590736

    Open questions at the time
    • Whether Dhx36-HDAC regulation operates in non-osteoblast contexts unknown
    • Full complement of transcription factors at the ALPL promoter not mapped
  3. 2012 High

    Demonstrating that TNAP knockout impairs CNS myelination and synaptogenesis established a neurological function for TNAP beyond its known skeletal role.

    Evidence Ultrastructural and morphometric analysis of Akp2−/− mouse spinal cord and cortex

    PMID:22696173

    Open questions at the time
    • Substrate responsible for CNS phenotype (PPi, ATP, PLP, or other) not identified
    • Cell-autonomous vs. non-cell-autonomous effects in neurons and oligodendrocytes not distinguished
  4. 2013 High

    Showing that TNAP activation requires cooperative zinc loading by ZnT1, metallothionein, and ZnT4 in the early secretory pathway identified the metallochaperone system essential for TNAP catalytic competence.

    Evidence Triple gene disruption and complementation with zinc-transport-competent re-expression; TNAP activity assays

    PMID:24204829

    Open questions at the time
    • Structural basis of zinc transfer to TNAP active site not resolved
    • Whether zinc loading is rate-limiting in vivo unknown
  5. 2013 Medium

    Functional characterization of HPP-associated ALPL missense mutations revealed that dominant-negative interference with wild-type TNAP, not merely loss of activity, underlies some cases of hypophosphatasia.

    Evidence Recombinant expression of six patient mutations with enzyme activity assays and co-transfection dominant-negative testing

    PMID:24022022

    Open questions at the time
    • Structural mechanism of dominant-negative effect on homodimer not determined
    • Genotype–phenotype correlation across larger patient cohorts not established
  6. 2015 High

    Demonstrating that TNAP and PHOSPHO1 cooperate non-redundantly, with combined inhibition abolishing 85% of mineralization, defined the dual-phosphatase logic of skeletal mineral initiation.

    Evidence Pharmacological epistasis with TNAP-specific and PHOSPHO1-specific inhibitors in osteoblast cultures and ex vivo metatarsals

    PMID:26457330

    Open questions at the time
    • In vivo double-knockout phenotype not reported at this point
    • Spatial and temporal segregation of the two phosphatases in the mineralizing front not resolved
  7. 2015 High

    Endothelial-specific TNAP overexpression driving arterial calcification and osteochondrogenic gene activation established that ectopic TNAP activity is sufficient to cause vascular disease, linking TNAP directly to pathological mineralization.

    Evidence Tie2-Cre conditional transgenic overexpression of human ALPL in mice with histology, gene expression, and cardiovascular phenotyping

    PMID:26675253

    Open questions at the time
    • Whether endothelial TNAP acts cell-autonomously or via paracrine PPi depletion not fully resolved
    • Threshold of TNAP activity required for pathological calcification undefined
  8. 2015 Medium

    Biophysical studies showed that GPI-anchored TNAP alters membrane lipid ordering and dynamics, suggesting a mechanism by which the membrane environment tunes TNAP function in matrix vesicles.

    Evidence ESR spectroscopy with spin-labeled phospholipids in DPPC proteoliposomes ± TNAP

    PMID:26389140

    Open questions at the time
    • Whether membrane modulation by TNAP is physiologically relevant in native MVs not demonstrated
    • Role of GPI anchor vs. protein ectodomain not dissected
  9. 2016 High

    Showing that TNAP overactivity in CD73-deficient patient cells depletes PPi and activates AKT/mTOR to drive ectopic calcification connected purine metabolism to pro-calcific signaling in arterial calcification of infancy.

    Evidence iPSC-derived MSCs from ACDC patients; TNAP activity, PPi, adenosine measurement; pharmacological rescue in teratoma model

    PMID:27965423

    Open questions at the time
    • Relative contribution of PPi depletion vs. AKT/mTOR activation not quantified
    • Therapeutic window for TNAP inhibition in ACDC patients unknown
  10. 2016 High

    TNAP overexpression in VSMCs induced chondrocyte-like trans-differentiation via PPi hydrolysis and BMP-2 upregulation, delineating a PPi→apatite→BMP-2→chondrogenesis pathway for vascular calcification.

    Evidence Gain- and loss-of-function with TNAP and BMP-2 inhibitor (noggin) in MOVAS, A7R5, and human MSCs

    PMID:27932058

    Open questions at the time
    • How apatite crystals induce BMP-2 transcription mechanistically unclear
    • In vivo validation of this specific pathway in human vascular disease lacking
  11. 2018 High

    Demonstrating that TNAP deficiency in MSCs elevates extracellular ATP, inactivates AMPKα, and causes a cell-fate switch to senescence revealed a non-mineralization role for TNAP in stem cell maintenance.

    Evidence Alpl−/− and Alpl+/− mice; ATP measurement, AMPKα assays, MSC differentiation/senescence; metformin rescue

    PMID:30210899

    Open questions at the time
    • Whether ATP internalization occurs via specific transporters or pannexin channels not defined
    • Relevance to human HPP bone marrow phenotype not established
  12. 2018 Medium

    Reduced extracellular ATP and diminished Pannexin-1 expression in TNAP+/− mouse brain linked TNAP haploinsufficiency to altered purinergic tone and seizure susceptibility in the CNS.

    Evidence CSF ATP measurement, ectonucleotidase/pannexin Western blots, seizure susceptibility testing in TNAP+/− mice

    PMID:29551976

    Open questions at the time
    • Mechanism by which TNAP regulates Panx1 expression not established
    • Substrate responsible (PLP, ATP, or other) not definitively identified
  13. 2019 High

    Direct dephosphorylation of SMAD2/3 by TNAP established a phosphatase–signaling axis through which TNAP negatively regulates TGF-β-driven fibrosis, expanding TNAP substrates beyond small molecules to signaling proteins.

    Evidence Co-IP of TNAP with SMAD2; gain- and loss-of-function phosphorylation assays in cardiac and skeletal muscle cells

    PMID:31289197

    Open questions at the time
    • Whether SMAD2/3 dephosphorylation occurs at the plasma membrane or intracellularly not resolved
    • Structural basis of TNAP–SMAD2 interaction unknown
  14. 2019 High

    Identification of the HLA-B27→sXBP1→RARB→TNAP axis in ankylosing spondylitis MSCs provided a disease-specific transcriptional pathway driving pathological new bone formation through TNAP.

    Evidence AS patient MSCs; pathway mapping; TNAP inhibitor treatment in vitro and in NOD-SCID mouse implant model

    PMID:31682238

    Open questions at the time
    • Mechanism of RARB-mediated TNAP induction not fully characterized
    • Whether this axis operates in all AS patients or specific subtypes unclear
  15. 2020 Medium

    Demonstrating that sphingomyelin content optimizes TNAP catalytic efficiency and mineral propagation revealed membrane lipid composition as a physiological modulator of TNAP function in matrix vesicles.

    Evidence TNAP in proteoliposomes of varying DMPC/cholesterol/SM composition; enzyme kinetics, calorimetry, turbidimetry, FTIR

    PMID:32710882

    Open questions at the time
    • Native MV lipid composition surrounding TNAP not mapped in vivo
    • Whether cells regulate MV lipid composition to tune TNAP activity unknown
  16. 2021 High

    Discovery that TNAP localizes to mitochondria in thermogenic adipocytes and functions as a phosphocreatine phosphatase driving futile creatine cycling revealed a completely unexpected metabolic role for TNAP in energy expenditure.

    Evidence Subcellular fractionation, mitochondrial phosphatase assays, TNAP inhibition, adipocyte-specific genetic ablation with whole-body calorimetry in mice

    PMID:33981039

    Open questions at the time
    • How TNAP is targeted to mitochondria rather than plasma membrane in adipocytes not resolved
    • Whether phosphocreatine is the sole thermogenic substrate unknown
  17. 2022 High

    Placing TNAP downstream of ADRA1A-Gαq signaling in the futile creatine cycle defined the adrenergic pathway controlling TNAP-dependent thermogenesis.

    Evidence Genetic and pharmacological manipulation of ADRA1A-Gαq signaling in adipocytes with energy expenditure measurement

    PMID:36344764

    Open questions at the time
    • Transcription factors directly activating ALPL downstream of Gαq not identified
    • Whether TNAP thermogenic function exists in human brown/beige fat not confirmed
  18. 2025 Medium

    Identification of ALPL on brain vascular endothelium as a receptor mediating AAV transcytosis across the blood-brain barrier revealed a receptor function for TNAP independent of its phosphatase activity.

    Evidence Direct binding assay of engineered AAV capsid (VCAP-102) to human ALPL; receptor-mediated transcytosis in cell barrier model and in vivo brain delivery

    PMID:40340250

    Open questions at the time
    • Whether endogenous ligands use TNAP for transcytosis unknown
    • Whether phosphatase activity is required for transcytosis not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how TNAP is differentially targeted to mitochondria vs. plasma membrane in different cell types, the structural basis of TNAP–SMAD2/3 interaction, and whether TNAP receptor-mediated transcytosis at the BBB operates for endogenous substrates.
  • Mechanism of cell-type-specific TNAP subcellular targeting unknown
  • No structural model of TNAP–SMAD complex
  • Full spectrum of TNAP protein substrates beyond SMAD2/3 not surveyed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 6 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 2
Partners
ANXA5DHX36ENPP1PHOSPHO1SLC30A1SLC30A4SMAD2

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 TNAP (encoded by ALPL) is the primary enzyme responsible for hydrolyzing both ATP and PPi in the matrix vesicle (MV) compartment during endochondral bone formation; kinetic analysis of MVs from TNAP-deficient mice showed the most pronounced reduction in hydrolysis of all physiologic substrates (ATP, ADP, PPi) compared to NPP1- or PHOSPHO1-deficient MVs. Kinetic analysis of substrate hydrolysis by isolated wild-type vs. TNAP-, NPP1-, and PHOSPHO1-deficient osteoblast-derived matrix vesicles at physiologic pH Journal of bone and mineral research High 19874193
2021 TNAP in thermogenic fat cells is localized to mitochondria (unlike other cell types) where it functions as a phosphocreatine phosphatase to initiate a futile creatine dephosphorylation/phosphorylation cycle that dissipates energy as heat; genetic ablation of TNAP in adipocytes reduces whole-body energy expenditure and causes rapid-onset obesity in mice. Biochemical phosphatase activity assays in isolated mitochondria, TNAP inhibition experiments, adipocyte-specific genetic ablation in mice with whole-body energy expenditure measurement, subcellular fractionation/localization Nature High 33981039
2022 TNAP acts as an effector protein of the futile creatine cycle downstream of ADRA1A-Gαq signaling; coordinated α1-adrenergic receptor and β3-AR signaling induces thermogenic gene expression including TNAP, and TNAP is required for the thermogenic output driven by this pathway in adipocytes. Genetic and pharmacological manipulation of ADRA1A-Gαq signaling in adipocytes; measurement of thermogenic gene expression and whole-body energy expenditure Nature metabolism High 36344764
2015 Transgenic overexpression of TNAP (ALPL) in vascular endothelial cells (via Tie2-Cre) is sufficient to drive generalized arterial calcification and upregulation of osteochondrogenic genes (Runx2, Bglap, Spp1, Opg, Col2a1) in aortas, demonstrating that endothelial TNAP promotes osteogenic trans-differentiation and vascular calcification. Conditional transgenic overexpression of human ALPL in endothelial cells using Tie2-Cre; histology, immunostaining, gene expression, cardiovascular phenotyping Journal of the American Heart Association High 26675253
2016 In ACDC patient-derived iMSCs lacking CD73, TNAP activity is increased and generates adenosine while depleting PPi (a calcification inhibitor), thereby promoting ectopic calcification; TNAP overactivity activates AKT/mTOR/p70S6K signaling to enhance mineralization. iPSC-derived mesenchymal stromal cells from ACDC patients; measurement of TNAP activity, PPi levels, adenosine production, AKT/mTOR pathway activation; in vivo teratoma model with pharmacological rescue Science signaling High 27965423
2016 TNAP overexpression or exogenous alkaline phosphatase in vascular smooth muscle cells (VSMCs) is sufficient to stimulate trans-differentiation into chondrocyte-like cells and induce mineralization; this is mediated through PPi hydrolysis leading to apatite crystal deposition and BMP-2 upregulation, with BMP-2 driving chondrogenesis (blocked by noggin). TNAP overexpression and exogenous AP addition to MOVAS/A7R5 VSMCs and human MSCs; TNAP inhibitor (levamisole); BMP-2 inhibitor (noggin); gene expression, mineralization assays Biochimica et biophysica acta. Molecular basis of disease High 27932058
2019 HLA-B27 activates TNAP in AS mesenchymal stem cells via the sXBP1/RARB/TNAP axis, promoting mineralization independently of Runx2; TNAP inhibitors (levamisole, pamidronate) blocked AS MSC mineralization in vitro and bony appositions in vivo in NOD-SCID mice implanted with AS MSCs. MSCs from AS patients; transcriptional pathway analysis; TNAP inhibitor treatment in vitro and in vivo animal model; mineralization assays The Journal of clinical investigation High 31682238
2019 TNAP colocalizes and physically interacts with SMAD2, and directly dephosphorylates SMAD2/3; TNAP inhibition increases SMAD2/3 phosphorylation while TNAP overexpression reduces it and decreases downstream fibrotic gene expression, demonstrating TNAP as a negative regulator of TGF-β/SMAD signaling to limit fibrosis. Co-localization and co-immunoprecipitation of TNAP with SMAD2; TNAP inhibitor (MLS-0038949) and overexpression; phosphorylation assays in cardiac and skeletal muscle cells Journal of cell science High 31289197
2011 The HDAC inhibitor MS-275 induces TNAP transcription via the RNA helicase Dhx36, which binds the MS-275 response element in the TNAP promoter; Dhx36 physically interacts with HDAC1 and HDAC4, and MS-275 decreases this interaction to relieve transcriptional repression of TNAP. TNAP promoter deletion constructs, luciferase reporter assay, DNA affinity precipitation assay, Co-IP of Dhx36 with HDACs, forced HDAC expression, in vivo bone regeneration models Journal of bone and mineral research High 21590736
2018 Alpl deficiency in mesenchymal stem cells (MSCs) enhances ATP release and reduces ATP hydrolysis, leading to elevated extracellular ATP that is internalized and increases intracellular ATP, which inactivates the AMPKα pathway and causes a cell fate switch (senescence and impaired differentiation) resulting in premature bone ageing phenotype. Alpl knockout and Alpl+/- mice; ATP measurement; AMPKα activity assay; MSC differentiation/senescence assays; metformin (AMPKα activator) rescue experiment Bone research High 30210899
2013 Full activation of TNAP in the early secretory pathway requires cooperative zinc handling by cytoplasmic ZnT1, metallothionein (MT), and ZnT4; cells deficient in all three show significantly reduced TNAP activity despite increased cytosolic zinc, and activity is restored only by zinc transport-competent re-expression of these proteins. Gene disruption and re-expression of ZnT1, MT, ZnT4 in cells; TNAP enzyme activity assay; zinc supplementation experiments PloS one High 24204829
2015 TNAP and PHOSPHO1 play non-redundant cooperative roles in initiating skeletal mineralization; combined inhibition of both enzymes essentially abolishes matrix mineralization (85% reduction), whereas individual inhibitors only partially reduce it, indicating cross-talk between the two phosphatases. PHOSPHO1-specific and TNAP-specific inhibitors applied to osteoblast cell cultures and ex vivo metatarsal models; mineralization assays with β-glycerol phosphate and phosphocholine as substrates Biochemistry and biophysics reports High 26457330
2015 Counter-regulatory roles of TNAP and NPP1 in tooth root cementogenesis: early TNAP expression creates a low PPi environment that promotes acellular cementum initiation, while later NPP1 expression increases PPi to restrict acellular cementum apposition; loss of TNAP in Alpl null mice inhibits acellular cementum while increasing cellular cementoid production. Analysis of Alpl null and Enpp1 null mice by histomorphometry and immunostaining; in vitro cementoblast cultures with gene/protein expression analysis International journal of oral science High 25504209
2012 Ablation of TNAP function in Akp2-/- mice results in decreased white matter, reduced myelinated axons in the spinal cord and cerebral cortex, abnormal paranodal ultrastructure, and increased proportion of immature cortical synapses, indicating TNAP is required for myelination and synaptogenesis. TNAP knockout (Akp2-/-) mice analyzed by light and electron microscopy, morphometry of myelinated axons and synapses during early postnatal development Cell and tissue research High 22696173
2017 TNAP regulates endochondral bone development in cranial base synchondroses by promoting hypertrophic chondrocyte apoptosis and VEGF expression via MAPK signaling; Alpl-/- primary chondrocytes exhibit diminished proliferation, aberrant gene expression, reduced hypertrophic apoptosis, and diminished MAPK signaling, all of which are corrected by mineral-targeted recombinant TNAP. Alpl-/- mice analyzed by micro-CT and histomorphometry; primary rib chondrocytes with TNAP deficiency; MAPK signaling and apoptosis assays; enzyme replacement rescue with recombinant TNAP Frontiers in physiology High 28377728
2018 In haploinsufficient TNAP+/- mice, extracellular ATP levels in cerebrospinal fluid are reduced and Pannexin-1 (Panx1) expression is specifically diminished in the brain, indicating that TNAP regulates extracellular ATP levels and Panx1 expression in the CNS and that TNAP+/- mice show enhanced susceptibility to ATP-induced seizures. TNAP+/- transgenic mice; extracellular ATP measurement in CSF; Western blotting for ectonucleotidases, pannexins, connexins, and vesicular nucleotide transporter; seizure susceptibility testing Frontiers in pharmacology Medium 29551976
2020 TNAP inhibition in cardiac fibroblasts attenuates their differentiation, migration, and proliferation, and reduces collagen gene expression; the antifibrotic mechanism involves suppression of TGF-β1/Smads signaling and upregulation of p-AMPK and p53; blocking p53 abrogates the antifibrotic effect of TNAP inhibition. TNAP inhibitor (tetramisole) in primary neonatal rat cardiac fibroblasts and rat MI model; adenovirus-mediated TNAP knockdown/overexpression; TGF-β1/Smads and p53 pathway analysis Cell death & disease Medium 31969558
2021 TNAP promotes cardiac fibrosis after myocardial infarction by activating TGF-β1/Smads and ERK1/2 signaling pathways in cardiac fibroblasts; adenoviral TNAP knockdown reduces fibrosis and improves cardiac function in mice, while overexpression worsens fibrosis. Adenovirus-mediated TNAP knockdown and overexpression in mouse MI model and primary cardiac fibroblasts; TGF-β1/Smads and ERK1/2 pathway activation assays; cardiac function assessment EBioMedicine Medium 33971401
2014 TNAP contributes to cardiomyocyte calcification and hypertrophy induced by α1-adrenoceptor activation (phenylephrine); CD73-derived adenosine suppresses TNAP activity, and CD73 inhibition alone induces hypertrophy and calcification that are blocked by TNAP inhibition, establishing a CD73-TNAP crosstalk axis. Neonatal rat cardiomyocytes treated with phenylephrine, adenosine analog, TNAP inhibitor (tetramisole), CD73 inhibitor; hypertrophy (surface area, ANP expression) and calcification (Alizarin Red) assays; CD73/TNAP gene and protein expression Molecular and cellular biochemistry Medium 24894822
2015 GPI-anchored TNAP increases membrane dynamics and decreases lipid ordering in model membranes (DPPC proteoliposomes), as measured by changes in rotational diffusion rates and order parameters; the effect extends to the hydrophobic core of the bilayer, indicating that GPI-anchored TNAP influences membrane physical properties relevant to its function. Electron Spin Resonance (ESR) with spin-labeled phospholipids in DPPC liposomes vs. TNAP-proteoliposomes; nonlinear least-squares simulations of ESR spectra Physical chemistry chemical physics Medium 26389140
2019 ALPL overexpression in high-grade serous ovarian cancer cells inhibits cell migration, invasion, and EMT by reducing FZD2 and WNT5A expression and suppressing downstream pSTAT3, identifying ALPL as a suppressor of the non-canonical WNT5A-FZD2-STAT3 axis. ALPL overexpression in SKOV3 and HEY HGSOC cell lines; migration/invasion assays; siRNA knockdown of FZD2; recombinant WNT5A rescue; gene ontology analysis of differential gene expression Biochemical and biophysical research communications Medium 30979497
2018 lncRNA HOTAIR epigenetically represses ALPL by reducing histone H3K4 methylation at the ALPL promoter; HOTAIR knockdown increases ALPL promoter activity, ALP activity, and mineralization in osteoblastic SaOS-2 cells. HOTAIR siRNA knockdown; luciferase reporter assay with ALPL promoter; chromatin H3K4 methylation analysis; ALP activity and mineralization assays Calcified tissue international Medium 29846771
2025 ALPL expressed on brain vascular endothelium serves as a receptor mediating transcytosis of engineered AAV vectors (VCAP-102) across the blood-brain barrier; direct binding of VCAP-102 to human ALPL was demonstrated and shown to initiate receptor-mediated transcytosis in a cell barrier model. AAV capsid evolution platform; identification of ALPL as primary receptor by molecular/genetic methods; direct binding assay of VCAP-102 to human ALPL; receptor-mediated transcytosis assay in cell barrier model; in vivo brain delivery in rodents and primates Molecular therapy Medium 40340250
2013 Six missense mutations in TNSALP (ALPL) identified in Chinese HPP patients (Y28D, A111T, T389N, M219V, R136L, Y388H) show reduced enzymatic activity in vitro primarily due to decreased expression of mature (80 kDa) protein forms; three mutations (Y28D, A111T, T389N) also exhibit dominant-negative effects on co-transfected wild-type TNAP. Plasmid expression of wild-type and mutant TNSALP in cells; ALP enzyme activity assay; Western blot for immature (66 kDa) and mature (80 kDa) forms; co-transfection dominant-negative assay Cellular physiology and biochemistry Medium 24022022
2016 An intronic branch-point deletion in ALPL (c.793del-14_33 in intron 7) causes exon 8 skipping, producing a C-terminally truncated TNAP protein of 275 amino acids (TNAP275) that has no enzymatic activity and no dominant-negative effect on wild-type TNAP. ALPL cDNA sequencing from patient PBMCs; recombinant expression of TNAP275; enzyme activity assay; co-transfection dominant-negative assay Bone Medium 27777120
2017 TNAP-harboring proteoliposomes containing both TNAP and annexin V (AnxA5) show more complex surface structures by AFM and lower affinity for type II collagen fibers compared to AnxA5-only proteoliposomes, indicating that TNAP insertion into the membrane modulates membrane properties and protein-collagen interactions relevant to matrix vesicle function. Atomic force microscopy (AFM) of DPPC/DPPS proteoliposomes with TNAP and/or AnxA5; collagen binding assays Biochimica et biophysica acta. Biomembranes Medium 28549727
2020 Membrane lipid composition (particularly sphingomyelin content) modulates TNAP activity and its ability to drive calcium phosphate mineral precipitation; DMPC:SM proteoliposomes show highest TNAP catalytic efficiency and mineral propagation efficiency, correlating with highest membrane organization. TNAP incorporated into proteoliposomes of varying lipid composition (DMPC, DMPC:Chol, DMPC:SM, DMPC:Chol:SM); calorimetry; turbidimetry; FTIR spectroscopy; enzyme kinetics Archives of biochemistry and biophysics Medium 32710882
2020 CircSIPA1L1 acts as a miRNA sponge for miR-204-5p to upregulate ALPL expression, thereby promoting osteogenic differentiation of stem cells from apical papilla (SCAPs); knockdown of circSIPA1L1 or overexpression of miR-204-5p suppresses osteogenic differentiation. Dual-luciferase reporter assay confirming circSIPA1L1–miR-204-5p interaction; circSIPA1L1/miR-204-5p knockdown and overexpression; Western blot and ALP staining; FISH for localization Stem cell research & therapy Low 33138854

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. Molecular cell 463 25498145
2013 CORVET and HOPS tethering complexes - coordinators of endosome and lysosome fusion. Journal of cell science 416 23645161
2004 Xanthohumol and related prenylflavonoids from hops and beer: to your good health! Phytochemistry 407 15231405
2013 Tethering complexes in the endocytic pathway: CORVET and HOPS. The FEBS journal 156 23351085
2010 Kinetic analysis of substrate utilization by native and TNAP-, NPP1-, or PHOSPHO1-deficient matrix vesicles. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 109 19874193
2021 Mitochondrial TNAP controls thermogenesis by hydrolysis of phosphocreatine. Nature 103 33981039
2005 Sec17p and HOPS, in distinct SNARE complexes, mediate SNARE complex disruption or assembly for fusion. The EMBO journal 100 15889152
2012 The HOPS proteins hVps41 and hVps39 are required for homotypic and heterotypic late endosome fusion. Traffic (Copenhagen, Denmark) 98 23167963
2019 CORVET, CHEVI and HOPS - multisubunit tethers of the endo-lysosomal system in health and disease. Journal of cell science 96 31092635
1998 Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia. European journal of human genetics : EJHG 96 9781036
2023 Immunosuppressive CD10+ALPL+ neutrophils promote resistance to anti-PD-1 therapy in HCC by mediating irreversible exhaustion of T cells. Journal of hepatology 94 37689322
2003 Inhibitors of nitric oxide production from hops (Humulus lupulus L.). Biological & pharmaceutical bulletin 91 12520174
2015 Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity. The Journal of biological chemistry 85 26463206
2017 Scc2/Nipbl hops between chromosomal cohesin rings after loading. eLife 83 28914604
2019 HOPS: automated detection and authentication of pathogen DNA in archaeological remains. Genome biology 82 31842945
2015 Transgenic Overexpression of Tissue-Nonspecific Alkaline Phosphatase (TNAP) in Vascular Endothelium Results in Generalized Arterial Calcification. Journal of the American Heart Association 76 26675253
2022 Structure of the HOPS tethering complex, a lysosomal membrane fusion machinery. eLife 72 36098503
2019 Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis. Circulation. Genomic and precision medicine 71 32141789
2018 Alpl prevents bone ageing sensitivity by specifically regulating senescence and differentiation in mesenchymal stem cells. Bone research 71 30210899
2016 Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC. Science signaling 71 27965423
2020 TNAP inhibition attenuates cardiac fibrosis induced by myocardial infarction through deactivating TGF-β1/Smads and activating P53 signaling pathways. Cell death & disease 61 31969558
2019 The Multiple Biological Targets of Hops and Bioactive Compounds. Chemical research in toxicology 55 30608650
2019 HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis. The Journal of clinical investigation 55 31682238
2015 Counter-regulatory phosphatases TNAP and NPP1 temporally regulate tooth root cementogenesis. International journal of oral science 53 25504209
2022 TNAP as a therapeutic target for cardiovascular calcification: a discussion of its pleiotropic functions in the body. Cardiovascular research 50 33070177
2023 The Global ALPL gene variant classification project: Dedicated to deciphering variants. Bone 47 37898381
2024 De novo biosynthesis of the hops bioactive flavonoid xanthohumol in yeast. Nature communications 46 38177132
2022 ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP. Nature metabolism 46 36344764
2011 Histone deacetylase inhibitor MS-275 stimulates bone formation in part by enhancing Dhx36-mediated TNAP transcription. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 46 21590736
2012 Ablation of TNAP function compromises myelination and synaptogenesis in the mouse brain. Cell and tissue research 45 22696173
2014 Improvement of the skeletal and dental hypophosphatasia phenotype in Alpl-/- mice by administration of soluble (non-targeted) chimeric alkaline phosphatase. Bone 44 25433339
2016 TNAP stimulates vascular smooth muscle cell trans-differentiation into chondrocytes through calcium deposition and BMP-2 activation: Possible implication in atherosclerotic plaque stability. Biochimica et biophysica acta. Molecular basis of disease 43 27932058
2019 HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins. Proceedings of the National Academy of Sciences of the United States of America 42 30610181
2017 Genetic analysis of adults heterozygous for ALPL mutations. Journal of bone and mineral metabolism 42 29236161
2021 Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation. EMBO molecular medicine 41 33851776
2023 Consecutive functions of small GTPases guide HOPS-mediated tethering of late endosomes and lysosomes. Cell reports 40 36640308
2017 Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia. American journal of medical genetics. Part A 37 28127875
2021 TNAP is a novel regulator of cardiac fibrosis after myocardial infarction by mediating TGF-β/Smads and ERK1/2 signaling pathways. EBioMedicine 36 33971401
1999 Differential expression and activity of tissue-nonspecific alkaline phosphatase (TNAP) in rat odontogenic cells in vivo. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 36 10567438
2019 Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients. Calcified tissue international 35 31707452
2017 Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline phosphatase (TNAP) inhibitor. Bioorganic & medicinal chemistry letters 35 29174347
2005 HOPS: a novel cAMP-dependent shuttling protein involved in protein synthesis regulation. Journal of cell science 34 16014383
2019 Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene. Scientific reports 33 31267001
2020 AP-3 vesicle uncoating occurs after HOPS-dependent vacuole tethering. The EMBO journal 32 32840906
2020 Circular RNA SIPA1L1 regulates osteoblastic differentiation of stem cells from apical papilla via miR-204-5p/ALPL pathway. Stem cell research & therapy 32 33138854
2017 Topographic analysis by atomic force microscopy of proteoliposomes matrix vesicle mimetics harboring TNAP and AnxA5. Biochimica et biophysica acta. Biomembranes 31 28549727
2013 Cooperative functions of ZnT1, metallothionein and ZnT4 in the cytoplasm are required for full activation of TNAP in the early secretory pathway. PloS one 31 24204829
2011 MSCA-1/TNAP selection of human jaw periosteal cells improves their mineralization capacity. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 31 21220938
2023 ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma. Nature communications 30 37291203
2006 Homozygosity for TNSALP mutation 1348c>T (Arg433Cys) causes infantile hypophosphatasia manifesting transient disease correction and variably lethal outcome in a kindred of black ancestry. The Journal of pediatrics 30 16769381
2019 HOPS/TMUB1 retains p53 in the cytoplasm and sustains p53-dependent mitochondrial apoptosis. EMBO reports 29 31867855
2004 TNAP, a novel repressor of NF-kappaB-inducing kinase, suppresses NF-kappaB activation. The Journal of biological chemistry 29 15208311
2002 Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients. European journal of human genetics : EJHG 28 12357339
2023 C9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy. Nature communications 27 37821429
2021 Bi-allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis-like disease. EMBO molecular medicine 27 33938619
2015 The Functional co-operativity of Tissue-Nonspecific Alkaline Phosphatase (TNAP) and PHOSPHO1 during initiation of Skeletal Mineralization. Biochemistry and biophysics reports 27 26457330
2020 Genotype-Phenotype Associations in 72 Adults with Suspected ALPL-Associated Hypophosphatasia. Calcified tissue international 25 33191482
2018 Incidence of Mutations in the ALPL, GGPS1, and CYP1A1 Genes in Patients With Atypical Femoral Fractures. JBMR plus 25 30680361
2022 Arabidopsis HOPS subunit VPS41 carries out plant-specific roles in vacuolar transport and vegetative growth. Plant physiology 24 35417008
2019 Vps8 overexpression inhibits HOPS-dependent trafficking routes by outcompeting Vps41/Lt. eLife 24 31194677
2020 Yeast phosphatidic acid phosphatase Pah1 hops and scoots along the membrane phospholipid bilayer. Journal of lipid research 23 32540926
2020 Dental defects in the primary dentition associated with hypophosphatasia from biallelic ALPL mutations. Bone 23 33160095
2017 Tissue Nonspecific Alkaline Phosphatase (TNAP) Regulates Cranial Base Growth and Synchondrosis Maturation. Frontiers in physiology 23 28377728
2012 Hepatocyte odd protein shuttling (HOPS) is a bridging protein in the nucleophosmin-p19 Arf network. Oncogene 23 22890319
2021 TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism. International journal of molecular sciences 22 33477631
2018 Synthesis and Antiproliferative Activity of Minor Hops Prenylflavonoids and New Insights on Prenyl Group Cyclization. Molecules (Basel, Switzerland) 22 29597299
2015 Rediscovering TNAP in the Brain: A Major Role in Regulating the Function and Development of the Cerebral Cortex. Sub-cellular biochemistry 22 26219708
2014 Caenorhabditis elegans HOPS and CCZ-1 mediate trafficking to lysosome-related organelles independently of RAB-7 and SAND-1. Molecular biology of the cell 22 24501423
2008 Genetic and epigenetic stability of cryopreserved and cold-stored hops (Humulus lupulus L.). Cryobiology 22 18822279
1993 Linkage relationships between ALPL, ENO1, GPI, PGD, and TGFB1 on porcine chromosome 6. Genomics 22 8104872
2015 Multiple Functions of MSCA-1/TNAP in Adult Mesenchymal Progenitor/Stromal Cells. Stem cells international 21 26839555
2014 CD73-TNAP crosstalk regulates the hypertrophic response and cardiomyocyte calcification due to α1 adrenoceptor activation. Molecular and cellular biochemistry 21 24894822
2022 Hops extract and xanthohumol ameliorate bone loss induced by iron overload via activating Akt/GSK3β/Nrf2 pathway. Journal of bone and mineral metabolism 20 35106609
2021 TNAP: A New Multitask Enzyme in Energy Metabolism. International journal of molecular sciences 20 34638808
2024 Loss of the HOPS complex disrupts early-to-late endosome transition, impairs endosomal recycling and induces accumulation of amphisomes. Molecular biology of the cell 19 38198575
2013 Characterization of six missense mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in Chinese children with hypophosphatasia. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 19 24022022
2019 ALPL regulates the aggressive potential of high grade serous ovarian cancer cells via a non-canonical WNT pathway. Biochemical and biophysical research communications 18 30979497
2019 TNAP limits TGF-β-dependent cardiac and skeletal muscle fibrosis by inactivating the SMAD2/3 transcription factors. Journal of cell science 18 31289197
2018 lncRNA HOTAIR Inhibits Mineralization in Osteoblastic Osteosarcoma Cells by Epigenetically Repressing ALPL. Calcified tissue international 18 29846771
2016 A homozygous intronic branch-point deletion in the ALPL gene causes infantile hypophosphatasia. Bone 18 27777120
2013 Different functions of HOPS isoforms in the cell: HOPS shuttling isoform is determined by RIP cleavage system. Cell cycle (Georgetown, Tex.) 18 24240191
2009 Association of ALPL and ENPP1 gene polymorphisms with bone strength related skeletal traits in a Chuvashian population. Bone 18 19931660
2025 Highly conserved brain vascular receptor ALPL mediates transport of engineered AAV vectors across the blood-brain barrier. Molecular therapy : the journal of the American Society of Gene Therapy 17 40340250
2019 Cloning, Purification, and Characterization of Recombinant Thermostable β-Xylanase Tnap_0700 from Thermotoga naphthophila. Applied biochemistry and biotechnology 17 31240547
2007 Ability of prenylflavanones present in hops to induce apoptosis in a human Burkitt lymphoma cell line. Planta medica 17 17715491
2022 Gene Therapy Using Recombinant AAV Type 8 Vector Encoding TNAP-D10 Improves the Skeletal Phenotypes in Murine Models of Osteomalacia. JBMR plus 16 36699639
2015 Effects of GPI-anchored TNAP on the dynamic structure of model membranes. Physical chemistry chemical physics : PCCP 16 26389140
2010 Inhibitors of hyaluronan export from hops prevent osteoarthritic reactions. Molecular nutrition & food research 16 20848398
2020 Lipid composition modulates ATP hydrolysis and calcium phosphate mineral propagation by TNAP-harboring proteoliposomes. Archives of biochemistry and biophysics 15 32710882
2022 BORC-ARL8-HOPS ensemble is required for lysosomal cholesterol egress through NPC2. Molecular biology of the cell 14 35653304
2019 Loss of tissue-nonspecific alkaline phosphatase (TNAP) enzyme activity in cerebral microvessels is coupled to persistent neuroinflammation and behavioral deficits in late sepsis. Brain, behavior, and immunity 14 31778743
2018 Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels. Frontiers in pharmacology 14 29551976
2018 Four novel mutations in the ALPL gene in Chinese patients with odonto, childhood, and adult hypophosphatasia. Bioscience reports 14 29724887
2017 Monoallelic FGFR3 and Biallelic ALPL mutations in a Thai girl with hypochondroplasia and hypophosphatasia. American journal of medical genetics. Part A 14 28763161
2019 Genetic correction of induced pluripotent stem cells mediated by transcription activator-like effector nucleases targeting ALPL recovers enzyme activity and calcification in vitro. Molecular genetics and metabolism 13 31178256
2024 New insights into the landscape of ALPL gene variants in patients with hypophosphatasia from the Global HPP Registry. American journal of medical genetics. Part A 12 38884565
2023 The hookup model of the HOPS complex in autophagosome-lysosome fusion. Autophagy 12 38083843
2022 The HOPS tethering complex is required to maintain signaling endosome identity and TORC1 activity. The Journal of cell biology 12 35404387
2020 Synthesis, characterization, in vitro tissue-nonspecific alkaline phosphatase (TNAP) and intestinal alkaline phosphatase (IAP) inhibition studies and computational evaluation of novel thiazole derivatives. Bioorganic chemistry 12 32711087
2016 The Expression of PHOSPHO1, nSMase2 and TNAP is Coordinately Regulated by Continuous PTH Exposure in Mineralising Osteoblast Cultures. Calcified tissue international 12 27444010