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FLASH GENE
Symbol HSPA4 contributors: mct/npt/shn - updated : 15-05-2018
HGNC name heat shock 70kDa protein 4
HGNC id 5237
Location 5q31.1      Physical location : 132.387.661 - 132.440.708
Synonym name
  • heat shock 70 kDa protein 4
  • heat shock 70-related protein APG-2
  • heat shock 70kD protein 4
  • heat shock protein, 110 kDa
    • Synonym symbol(s) RY, APG2, HSP70, hsp70RY, HS24/P52, HSPG1R2, MGC131852, APG-2
    DNA
    TYPE functioning gene
    STRUCTURE 53.05 kb     19 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map cen - D5S1984 - D5S2002 - HSPA4 - D5S2117 - D5S2053 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    19 splicing 3385 94 840 - Lee (2008)
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Digestiveliver    
     mouth   highly
     stomach   predominantly
    Nervousbrain    
    Reproductivemale systemprostate   
    Respiratorylung    
    Skin/Tegumentskin   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Lymphoid    
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/Immunelymphocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • an N-terminal ATP-binding domain
  • a C-terminal peptide-binding domain characteristic of HSP proteins
    • HOMOLOGY
    interspecies ortholog to Hspa4, Rattus norvegicus
    ortholog to Hspa4, Mus musculus
    ortholog to HSPA4, Pan troglodytes
    ortholog to hspa4b, Danio rerio
    intraspecies homolog to aconitase,structurally
    Homologene
    FAMILY
  • heat shock protein 70 family
    • CATEGORY chaperone/stress
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    basic FUNCTION
  • may be acting in protein folding, translocation, and assembly into complexes
  • involved in the targeting of a subset of mitochondrial preproteins to the TOM70 receptor
  • inhibiting alpha-Synuclein (AS) fibril formation via preventing the formation of prefibrillar AS (PreAS), binding with PreAS to impede nuclei formation, and binding with nuclei to retard fibril elongation
  • plays an important role in the pathogenesis of tauopathies
  • in erythroid precursors undergoing terminal differentiation, Hsp70 prevents active caspase-3 from cleaving GATA-1 and inducing apoptosis
  • plays a role in the regulation of mTORC2/Akt signaling in response to heat shock
  • a role in misfolding of the islet betta-cell peptide human amylin
  • considerably accumulates at the mitotic centrosome during prometaphase to metaphase and is required for bipolar spindle assembly
  • HSPA4 chaperone is sensor of the NEDD8 cycle upon DNA damage
    • CELLULAR PROCESS protein, post translation, folding
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    pathway (NBN-HSF4-HSPA4/HSPA14 axis) to induce migration, invasion, and transformation, suggesting the activation of multiple signaling events induced by NBN overexpression
    a component
  • component of mTORC2 that is required for proper assembly and activity of the kinase both constitutively and following heat shock
  • PGLYRP1 forms with HSPA4 a stable complex with cytotoxic and antitumor activity
  • HSPA4 chaperone is sensor of the NEDD8 cycle upon DNA damage
    • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP
    • protein
  • Keratin polypeptides 8 and 18, K8/18
  • heat shock transcription factor 1, HSF1
  • heat shock factor binding protein 1, HSBP1
  • Fanconi anemia (FA) complementation group C gene product, FANCC
  • apobec-1-binding protein-2, ABBP-2
  • NAD(P)H:quinone oxidoreductase 1, NQO1
  • CHIP, Parkin, and Pael-R
  • CD40
  • docking protein CAIR-1
  • SMAD family member 3, SMAD3
  • Hsp40 and TPR1
  • Hypoxia inducible factor 1 alpha, HIF-1alpha
  • superoxide dismutase 1, SOD1
  • the mutants of multiple endocrine neoplasia type 1, MEN1
  • interferon gamma receptor accessory factor-1, AF-1
  • bcl-2-associated athanogene 5, BAG5
  • antigen presenting cells, APC and lectin-type oxidized LDL receptor 1, LOX-1
  • associate to RICTOR, as components of mTORC2, in intact mammalian cells
  • Endonuclease G, EndoG
  • bcl-2-associated athanogene 2, BAG2
  • specific interaction between HSPA4 and MBP suggestive of a possible role for HSPA4 in the immunopathology associated with multiple sclerosis (Lund 2006)
  • umor necrosis factor receptor-associated factor 6, TRAF6
  • protein kinase C, PKC
  • heat shock protein 110 kDa, Hsp110
  • LIM Kinase 1, LIMK1
  • substrate for parkin
  • TTC4 is a nucleoplasmic protein which interacts with HSP90AA1 and HSPA4, and also with the replication protein CDC6
  • TPR repeat protein 2, TRP2
  • corepressor REST, CoREST
  • interacting with ENPP1 (by affecting ENPP1 expression, may be a novel mediator of altered insulin signaling) (Marucci 2009)
  • HSPA4 binds MGP and enhances BMP activity, thereby functioning as a potential link between cellular stress, inflammation, and BMP signaling
  • HSPH1 suppressed the expanded polyQ tract-induced protein aggregation and apoptosis through the induction of HSPA4
  • misfolded human amylin oligomers
  • interaction between HSBP1 and the ATPase domain of the major heat shock protein HSPA4 up-regulates nucleotide exchange and reduces the affinity between HSPA4 and the peptide in its peptide-binding site
  • cytoplasmic HSPA4 plays a critical role in selecting immature forms of SLC12A3 for ERAD
  • HSPBP1 incapacitates the HSPA4-PGLYRP1 complex
  • functional interaction between TCL1A and HSPA4 and TCL1A is a novel HSPA4 client protein
  • OLA1 stabilizes HSPA4, leading to upregulation of HSPA4 as well as increased survival during heat shock
  • HIF1A positively regulates the induction of NFAT5 and HSPA4 by placental hypoxia
  • ubiquitin-proteasomal regulation of DNAJC7 and HSPA4 are important contributors to the regulation of cytoplasmic NR1I3 levels
  • may associate with NEDD1 and TUBG1, two pericentriolar material (PCM) components essential for centrosome maturation and MT nucleation
  • DNAJB6 and HSPA4 cooperate to suppress SNCA aggregation
  • STIP1 is a co-chaperone of HSPA4 and HSP90AA1 that regulates a number of cell biology processes via interactions with cellular proteins
  • DNAJA2 and DNAJA1 were both important for CFTR folding, however overexpressing DNAJA2 but not DNAJA1 enhanced CFTR degradation at the endoplasmic reticulum by HSPA4/HSPA8 and the E3 ubiquitin ligase STUB1
    • cell & other
    REGULATION
    Other modulated by bcl-2-associated athanogene 1, BAG1 (
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in acute spinal cord injury
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerhemopathy 
    inhibition of HSPA4 may represent an alternative effective therapy for chronic lymphocytic leukemia and lymphomas via its ability to inhibit the oncogenic functions of TCL1A
    ANIMAL & CELL MODELS