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FLASH GENE
Symbol CTSK contributors: mct/pgu - updated : 06-10-2015
HGNC name cathepsin K
HGNC id 2536
Corresponding disease
PYCD pycnodysostosis
Location 1q21.3      Physical location : 150.768.686 - 150.780.812
Synonym name
  • cathepsin O1
  • cathepsin K (pycnodysostosis)
  • cathepsin O2
  • cathepsin X
  • Synonym symbol(s) CTSO, CTSO1, CTSO2, PKND, CATK, CTS02, PYCD, MGC23107
    EC.number 3.4.22.38
    DNA
    TYPE functioning gene
    STRUCTURE 12.13 kb     8 Exon(s)
    Genomic sequence alignment details
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   transcription factor
    text structure
  • two AP-1sites
  • two consensus Sp1 binding sites and a rich GtC region are identified in the promoter region as potential regulatory elements
  • three NFATC1 binding sites upstream the transcriptional start site
  • MAPPING cloned Y linked Y status confirmed
    Map cen - D1S442 - D1S2344 - CTSK /CTSS - MCL1 - D1S498 - D1S2347 - D1S2343 /D1S2345 - qter
    Authors (PMID: 8703060)
    Physical map
    ANP32E 1q21.1 acidic (leucine-rich) nuclear phosphoprotein 32 family, member E CA14 1q21 carbonic anhydrase XIV APH-1A 1p36.13-q31.3 likely ortholog of C. elegans anterior pharynx defective 1A FLJ23221 1q21.3 hypothetical protein FLJ23221 LOC148523 1q21.3 hypothetical protein BC017397 MRPS21 1q21 mitochondrial ribosomal protein S21 PRPF3 KIAA0460 1q21.3 KIAA0460 protein FLJ12528 1q21.3 threonyl-tRNA synthetase ECM1 1q21.1-q21.2 extracellular matrix protein 1 TSRC1 1q21.3 thrombospondin repeat containing 1 FLJ13544 1q21.3 hypothetical protein FLJ13544 MCL1 1q21 myeloid cell leukemia sequence 1 (BCL2-related) ENSA 1q21.2 endosulfine alpha GPP34R 1q21.3 GPP34-related protein DKFZP434A1315 1q21.3 hypothetical protein DKFZp434A1315 CTSS 1q21 cathepsin S CTSK 1q21 cathepsin K (pycnodysostosis) ARNT 1q21 aryl hydrocarbon receptor nuclear translocator HCP1 1q21.3 cytochrome c, somatic pseudogene SETDB1 1q21 SET domain, bifurcated 1 LASS2 1q11 LAG1 longevity assurance homolog 2 (S. cerevisiae) ANXA9 1q21 annexin A9 FLJ11280 1q21.3 hypothetical protein FLJ11280 BNIPL 1q21.2 BCL2/adenovirus E1B 19kD interacting protein like HTCD37 1q21 TcD37 homolog FLJ20519 1q21.3 hypothetical protein FLJ20519 SPEC1 1q21.2 hypothetical protein FLJ20519 AF1Q 1q21 hypothetical protein FLJ20519 MGC29891 1q21.3 hypothetical protein MGC29891 SEMA6C 1q21.2 sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6C FLJ23467 1q21.3 hypothetical protein FLJ23467 LOC388695 1 similar to hypothetical protein SB145 SCNM1 1q21.3 sodium channel modifier 1 TMOD4 1q12 tropomodulin 4 (muscle) TCFL1 1q21 transcription factor-like 1 PIP5K1A 1q22-q24 phosphatidylinositol-4-phosphate 5-kinase, type I, alpha
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 - 1702 - 329 - 2009 19338743
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Respiratorylung     Homo sapiens
    Skin/Tegumentskin     Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  highly
    Connectivebone  highly
    Epithelialbarrier liningepidermis   Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Skeletonosteoclast Homo sapiens
    Skin/Tegument  Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • two potential N-glycosylation sites
  • cathepsin propeptide inhibitor domain
  • peptidase C1 domain
  • a catalytic site consists of two domains folded together to give a V-shaped active site cleft configuration
  • conjugated GlycoP
    isoforms Precursor a 15AA N terminal and a 99-residue propreptide
    HOMOLOGY
    intraspecies homolog to CSTL,CSTS
    Homologene
    FAMILY
  • papain cysteine protease family
  • peptidase C1 family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,lysosome
    text synthesizing and secreting cathepsin K into the extracellular compartment at the attachment site between osteoclasts and the bone surface, where in the organic matrix is subsequently degraded by cathepsin K
    basic FUNCTION
  • playing an important role in the homeostasis of the dermal extracellular matrix and the dynamic equilibrium between matrix synthesis and proteolytic degradation
  • P cysteine proteinase, exhibiting strong degradative activity against the extracellular matrix and involved in osteoclast-mediated bone destruction
  • likely major lysosomal protein in bone matrix resorption
  • critical protease in synovial fibroblast-mediated collagen degradation
  • having dual functions as a cysteine protease and a regulator of osteoclasts survival, playing a role as a potential regulator of osteoclasts apoptosis and senescence
  • may mediate osteoclasts apoptosis and senescence through the Tp53-dependent pathway
  • lysosomal cysteine protease with strong collagenolytic activity that mediates bone resorption in osteoclasts
  • may play a role in maintaining homeostasis of the extracellular matrix outside of bone
  • may play an important role in melanoma invasion and metastasis by mediating intracellular degradation of matrix proteins after phagocytosis
  • responsible for the degradation of type I collagen in osteoclast-mediated bone resorption
  • playing a role in bone resorption demonstrating its ability to regulate the initiation and termination of the resorption process in an autocrine manner
  • with CTSL, and CTSK, implicated in atherogenesis
  • collagenase activity of cathepsin K requires a highly specific interaction with chondroitin 4-Sulfate (C4-s)
  • late differentiation marker during osteoclastogenesis
  • plays an essential role in abdominal aortic aneurysm (AAA) formation by promoting T-cell proliferation, vascular SMC apoptosis, and elastin degradation and by affecting vascular cell protease expression and activities
  • cysteine peptidase cathepsin K that is a major player in extracellular proteolysis
  • CTSB, CTSK, CTSL1, CTSS may be putative leptin activity regulators in white adipose tissue (WAT)
  • cathepsin K ablation mitigates pressure overload-induced hypertrophy, possibly via inhibition of the mammalian target of rapamycin and ERK pathways
  • major lysosomal collagenase produced by osteoclasts, playing an important role in bone resorption
  • major collagenolytic protease in bone that facilitates physiological as well as pathological bone degradation
  • is organized into elongated C-shaped protease dimers that reveal a putative collagen-binding interface aided by glycosaminoglycans
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interaction with type I collagen is required for the release of cryptic Arg-Gly-Asp motifs during the initial attachment of osteoclasts and termination of resorption via the creation of autocrine signals originating from type I collagen degradation
  • both cathepsins K and S cleave elastin, albeit with different affinities and catalytic rates, but only cathepsin K cleaves triple helical type I and II collagens
  • multifunctional extracellular chaperone clusterin is a cathepsin K-binding protein
  • cathepsin S binds to cathepsin K in a catalytically productive manner to form an enzyme-enzyme complex
  • cathepsin cannibalism is a phenomenon, where cathepsin S degrades cathepsin K and, in the presence of ECM substrate proteins, can result in a reduction of total substrate proteolysis
  • cathepsin K exocytosis is controlled by PRKCD through modulation of the actin bundling protein myristoylated alanine-rich C-kinase substrate (MARCKS)
  • specific binding of CTSK at the edge of the fibrillar gap region of collagen fibers, which suggest initial cleavage events at the N- and C-terminal ends of tropocollagen molecules 3)
  • CTSK was responsible for the activation of pro-MMP9, with a key link between CTSK expression in tumors and bone and ECM remodeling, through MMP9 activation
  • cell & other
    REGULATION
    induced by NFATC1 binding in the promoter, after TNFSF11 activation via the Ca2+/calmodulin/calcineurin signaling pathway
    ASSOCIATED DISORDERS
    corresponding disease(s) PYCD
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in osteoclastoma
    tumoral     --over  
    in metastases of prostate cancer
    constitutional     --over  
    CTSK levels were increased in the serum of tuberculosis patients compared to controls
    constitutional     --over  
    were markedly elevated in human hearts of end-stage dilated cardiomyopathy
    constitutional   deletion    
    in osteoclasts enhances bone formation by increasing the generation of osteoclast-derived sphingosine-1-phosphate (S1P)
    constitutional     --over  
    in human abdominal aortic aneurysm (AAA) lesions
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    osteoarticularboneostéoporosis
    decreasing the activity of cathepsin K by specific inhibitors or antisense approaches could provide a beneficial treatment for pathologic processes (arthritis and osteoporosis)
    osteoarticularboneostéoporosis
    Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts and similarly augmented bone morphogenetic protein BMP2 release
    cancerskin 
    clinical use of CTSK inhibitors, a class of medication currently in clinical trials for the treatment of osteoporosis, may be a promising avenue for the treatment of melanoma
    immunologyautoimmunearticular
    CTSK may be targeted to treat rheumatoid arthritis and periodontitis simultaneously due to its shared osteoimmune role
    ANIMAL & CELL MODELS
  • osteopetrosis in cathepsin K deficient in mice
  • mice deficient in cathepsin K have reduced adipose tissue mass
  • AAA lesions from Ctsk-deficient mice showed reduced elastinolytic cathepsin activities compared with those from wild-type control mice
  • global deletion of Ctsk in mice decreases bone resorption, leading to osteopetrosis, but also increases the bone formation rate (BFR)
  • gene deletion of Ctsk in mice accelerated callus size resolution, significantly increased callus mineralized mass, and improved mechanical strength as compared to wild type mice