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FLASH GENE
Symbol PINK1 contributors: shn - updated : 18-10-2010
HGNC name PTEN induced putative kinase 1
HGNC id 14581
Corresponding disease
PARK6 Parkinson disease 6
Location 1p36.12      Physical location : 20.959.947 - 20.978.003
Synonym name
  • protein kinase BRPK
  • serine/threonine-protein kinase PINK1, mitochondrial
  • Parkinson disease (autosomal recessive) 6
  • Synonym symbol(s) BRPK, FLJ27236, PARK6
    EC.number 2.7.11.1
    DNA
    TYPE functioning gene
    STRUCTURE 18.06 kb     8 Exon(s)
    Genomic sequence alignment details
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    Map pter - D1S2732 - D1S3720 - PINK1 - D1S478 - D1S334 - cen
    Physical map
    KIAA0090 1p36.13 heparan sulfate proteoglycan 2 (perlecan) C1orf33 1p36.13 chromosome 1 open reading frame 33 AFAR3  aflatoxin B1 aldehyde reductase 3 AKR7A3 1p35.1-p36.23 aldo-keto reductase family 7, member A3 (aflatoxin aldehyde reductase) AKR7A2 1p36.1-p35 aldo-keto reductase family 7, member A2 (aflatoxin aldehyde reductase) FLJ20320 CAPZB 1p36.1 capping protein (actin filament) muscle Z-line, beta LOC388600 1 similar to protein of fungal metazoan origin like (11.1 kD) (2C514) NBL1 1p36.13-p36.11 neuroblastoma, suppression of tumorigenicity 1 HTR6 1p36-p35 5-hydroxytryptamine (serotonin) receptor 6 LOC255104 1p36.13 hypothetical protein LOC255104 FLJ20225 1p36.13 hypothetical protein FLJ20225 LOC254897 1p36.13 similar to OSJNBa0043A12.32 PLA2G2E 1p36.13 similar to OSJNBa0043A12.32 PLA2G2A 1p36.1-p35 phospholipase A2, group IIA (platelets, synovial fluid) PLA2G5 1p36-p34 phospholipase A2, group V PLA2G2D 1p36.12 phospholipase A2, group IID PLA2G2F 1p35 phospholipase A2, group IID LOC391013 1 similar to Group IIC secretory phospholipase A2 precursor (Phosphatidylcholine 2-acylhydrolase GIIC) (GIIC sPLA2) (PLA2-8) (14 kDa phospholipase A2) FLJ25429 FLJ32784 1p36.13 hypothetical protein FLJ32784 LOC388601 1 LOC388601 CaMKIINalpha 1p36.13 calcium/calmodulin-dependent protein kinase II FLJ12875 1p36.13 hypothetical protein FLJ12875 LOC163933 1p36.12 similar to cDNA sequence BC022623 CDA 1p36.2-p35 cytidine deaminase PINK1 1p36 PTEN induced putative kinase 1 DDOST 1p36.1 dolichyl-diphosphooligosaccharide-protein glycosyltransferase KIF17 1p36.13 kinesin family member 17 LOC388602 1 LOC388602 LOC388603 1 LOC388603 HP1-BP74 1p36.12 HP1-BP74 EIF4G3 11p15 eukaryotic translation initiation factor 4 gamma, 3 LOC388604 1 LOC388604 ECE1 1p36.1 endothelin converting enzyme 1 LOC391014 1 similar to protein phosphatase 1, regulatory (inhibitor) subunit 11 isoform 1; hemochromatosis candidate gene V; t-complex-associated-testis-expressed 5; inhibitor-3 LOC343381 1p36.12 similar to KIAA0454 protein LOC391015 1 similar to hypothetical protein AE2 LOC388605 1 similar to heparan-sulfate 6-sulfotransferase LOC391016 1 similar to KIAA0445 protein AE2 1p36.12 hypothetical protein AE2 ALPL 1p36.1 alkaline phosphatase, liver/bone/kidney RAP1GA1 1p36.1 RAP1, GTPase activating protein 1 USP31 1p36.12 ubiquitin specific protease 31 HSPG2 1p36.11-p35 heparan sulfate proteoglycan 2 (perlecan) LOC391017 1 hypothetical gene supported by X89401; NM_000982 ELA3B 1p36.12 elastase 3B, pancreatic ELA3A 1p36.12 elastase 3A, pancreatic (protease E) HSPC157 1p36.12 HSPC157 protein CDC42 1p36.1 cell division cycle 42 (GTP binding protein, 25kDa)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 - 2680 66 581 mitochondrial 2008 18003639
  • A full-length pre-protein (66 kDa) and an N-terminally truncated mature form (55 kDa) have been described in human brain
  • full-length precursor protein has weak intrinsic kinase activity
  • accumulation of FL-PINK1 might have a dominant negative effect on PINK1 protein function
  • - - - 53 - - 2011 21138942
  • PINK1 is cleaved between Ala-103 and Phe-104 to generate the 53 kDa deltaN-PINK1 protein, and PARL is responsible for PINK1 cleavage at position A103
  • deltaN-PINK1 product is the functionally active form of the protein conferring cell protection against stress
  • EXPRESSION
    Rna function highest expressed in hippocampus, substantia nigra, cerebellar purkinge cells
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestiveliver   highly
    Endocrinepancreas   highly
    Nervousbrain   highly
    Reproductivemale systemtestis  highly
    Respiratorylung    
    Urinarykidney   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Connectivebone   
    Epithelialsecretoryglandularendocrine 
    Epithelialsecretoryglandularexocrine 
    Muscularstriatumskeletal  
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N-terminal mitochondrial signal
  • a conserved kinase domain
  • a C-terminal domain that regulates autophosphorylation activity
  • HOMOLOGY
    interspecies ortholog to Pink1, Mus musculus
    ortholog to Pink1, Rattus norvegicus
    ortholog to pink1, Danio rerio
    ortholog to PINK1, Pan troglodytes
    Homologene
    FAMILY
  • protein kinase superfamily
  • Ser/Thr protein kinase family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,interspace
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,cytosolic
    text
  • precursor form of PINK1 translocates to the mitochondria and is processed into two cleaved forms of PINK1, which in turn localize more to the cytosolic than mitochondrial fraction
  • cytosolic and mitochondrially localized
  • with BECN1, localize to the mitochondrial compartment
  • localize to mitochondria, and upon entry into the organelle, is cleaved to produce a 53 kDa protein (deltaN-PINK1)
  • basic FUNCTION
  • acts with Parkin in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons
  • plays an essential role in maintaining neuronal survival by preventing neurons from undergoing oxidative stress
  • a possible regulatory role for the PINK1/Parkin pathway in mitochondrial fission
  • important for mitochondrial function and provides critical protection against both intrinsic and environmental stress
  • regulates calcium efflux from the mitochondria via the mitochondrial Na(+)/Ca(2+) exchanger
  • functional links between PINK1, Parkin and the selective autophagy of mitochondria
  • with PARK2 are intimately involved in preventing mitochondrial dysfunction
  • promotes proteasomal degradation of PARK2
  • PINK1 and HSPA9 accumulated in different cellular compartments, and these two proteins share, at least partially, the same pathway of mitochondrial import
  • PINK1 and HSPA9 are synthesized as a precursor protein which is cleaved into its mature form after import into mitochondria in a mitochondrial membrane potential-dependent manner
  • required for the recruitment of parkin to depolarize mitochondria prior to selective clearance of the functionally inactive organelles by autophagy
  • PINK1 and PARK2 are thus required for the removal of damaged mitochondria in dopaminergic cells, and inhibition of this pathway may lead to the accumulation of defective mitochondria which may contribute to Parkinson disease pathogenesis
  • restoration of autophagy in PINK1-silenced cells by PARK2 reverses ATP synthesis inhibition and the ubiquitination of MFN1 and MFN2 play a role in PINK1/PARK2-mediated mitophagy
  • PARK7 works in parallel to the PINK1/parkin pathway to maintain mitochondrial function in the presence of an oxidative environment
  • differential localization to the inner and outer mitochondrial membranes appears to regulate PINK1 stability and function
  • exerts its cytoprotective function not only in mitochondria but also in the cytoplasm through activation of CRTC2
  • key role for PINK1 in the regulation of mitochondrial homeostasis and energy metabolism under physiological conditions
  • PINK1 activity is crucial for postnatal myocardial development, through its role in maintaining mitochondrial function, and redox homeostasis in cardiomyocytes
  • crucial in the maintenance of mitochondrial function and redox homeostasis in cardiomyocytes
  • importance of PINK1 as a mitochondrial protein functioning to regulate the complex interplay between mitochondrial function, ROS production, and hypertrophic signaling in the heart
  • because PINK1 acts via PARK2 in arresting mitochondria, PINK1 was predicted to require PARK2 to promote RHOT1, RHOT2 degradation
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS mitochondrial transport
    PATHWAY
    metabolism
    signaling
  • PINK1/Parkin pathway plays conserved roles in regulating neuronal mitochondrial dynamics and function
  • by preventing mitochondrial movement, the PINK1/PARK2 pathway may quarantine damaged mitochondria prior to their clearance
  • a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interaction between PINK1 and Mitofilin
  • regulates the E3 ubiquitin-protein ligase function of parkin through direct phosphorylation
  • interacts with the mitochondrial protease presenilin-associated rhomboid-like protein (PARL) and loss of PARL results in aberrant PINK1 cleavage in mammalian cells
  • normal PINK1 localization and stability requires PARL catalytic activity
  • PARL cleaves PINK1, which is implicated in Parkinson disease, within its conserved membrane anchor, to regulate PINK1 trafficking
  • phosphorylates Miro (RHOT1 and RHOT2), a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface
  • association of PINK1 with SARM1 and TRAF6 is an important step for mitophagy
  • cell & other
    REGULATION
    induced by PTEN
    by FOXO3a is crucial for survival signals in lymphocytes, as depletion of PINK1 sensitizes these cells to death induced by deprivation of an essential growth factor
    ASSOCIATED DISORDERS
    corresponding disease(s) PARK6
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in ovarian tumor
    constitutional       loss of function
    elicits oxidative stress and mitochondrial turnover coordinated by the autophagic and fission/fusion machineries
    constitutional     --low  
    depletion of PINK1 induces moderate fragmentation of the mitochondrial network, mitochondrial membrane depolarization and increased production of reactive oxygen species
    constitutional     --low  
    markedly reduced in end-stage heart failure
    constitutional     --low  
    impairs mitochondrial fission, which causes defective assembly of the electron transport chain complexes, leading to abnormal bioenergetics
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Drosophila with loss-of-function of PINK1 gene exhibit indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects
  • removal of Drosophila PINK1 results in male sterility, apoptotic muscle degeneration, defects in mitochondrial morphology and increased sensitivity to multiple stresses including oxidative stress
  • inhibition of Drosophila Pink1 function results in energy depletion, shortened lifespan, and degeneration of select indirect flight muscles and dopaminergic neurons
  • inactivation of Drosophila PINK1 using RNAi results in progressive loss of dopaminergic neurons and in ommatidial degeneration of the compound eye
  • deletion of PINK1 gene in mice significantly impairs mitochondrial functions associated with impairment of mitochondrial respiration in the striatum and dopaminergic circuitry defects
  • transgenic expression of Parkin markedly ameliorated all PINK1 loss-of-function phenotypes in Drosophila PINK1 model
  • expression of human SOD1 suppresses neurodegeneration induced by drosophilia PINK1 inactivation
  • mdivi-1 (mitochondrial division inhibitor 1), a quinazolinone, rescue mitochondrial morphological and functional defects induced by mutations in PINK1
  • PINK1-/- mice have greater levels of oxidative stress and impaired mitochondrial function