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FLASH GENE
Symbol HSPA5 contributors: mct/pgu/shn - updated : 04-06-2019
HGNC name heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa)
HGNC id 5238
Location 9q33.3      Physical location : 127.997.126 - 128.003.666
Synonym name
  • immunoglobulin heavy chain binding protein
  • 78 kDa glucose-regulated protein
  • endoplasmic reticulum lumenal Ca(2+)-binding protein grp78
  • heat shock 70kD protein 5 (glucose-regulated protein, 78kD)
    • Synonym symbol(s) GRP78, IGH-BIP, D7G6, BIP, FLJ26106, MIF2
    DNA
    TYPE functioning gene
    STRUCTURE 6.53 kb     8 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site
    text structure
  • an ER stress response element (ERSE)
  • region between -371 and -109 of the proximal promoter contains major E2F1-responsive elements
  • promoter contains the ER stress element which is commonly present in the genes involved in unfolded protein response (UPR) that regulates protein secretion in cells
    • MAPPING cloned Y linked   status confirmed
    Map cen - D9S1825 - D9S1789 - HSPA5 - D9S266 - D9S1829 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 - 3965 - 654 - 1996 8816500
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveesophagus   highly
    Endocrinethyroid   highly
    Reproductivefemale systembreastmammary gland highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Skin/Tegumentkeratinocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text pancreas
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal ATPase domain
  • the C terminal substrate binding region
    • HOMOLOGY
    interspecies ortholog to Hspa5, Mus musculus
    ortholog to Hspa5, Rattus norvegicus
    ortholog to HSPA5, Pan troglodytes
    ortholog to hspa5, Danio rerio
    intraspecies homolog to HSP70
    Homologene
    FAMILY
  • heat shock protein 70 family
    • CATEGORY chaperone/stress , receptor
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,mitochondria,inner
    intracellular,cytoplasm,organelle,mitochondria,interspace
    intracellular,cytoplasm,organelle,mitochondria,matrix
    intracellular,cytoplasm,organelle,lumen
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    text
  • associated wiht HGC1 molecules
  • concentrated in the perinuclear region and co-localized with the ER marker proteins, calnexin and PDI (protein disulphide-isomerase), in cells under normal growth conditions
  • mitochondria-resided GRP78 is mainly located in the intermembrane space, inner membrane and matrix, but is not associated with the outer membrane
  • exists primarily as an ER protein with intracellular chaperone functions, and is upregulated in response to ER stress in order to diminish growth inhibitory signals, and promote cell survival
  • predominantly an endoplasmic reticulum lumen protein
  • is also present on the cell surface membrane of trophoblastic cells, where it is associated with invasive or fusion properties of these cells
    • basic FUNCTION
  • prevents apoptosis induced by calcium ionophore, ionomycin in prostate cancer cells
  • protective role for GRP78 in preventing endoplasmic reticulum stress-induced cell death
  • endoplasmic reticulum chaperone protein, involved in protein folding and assembly in the ER
  • playing a role in facilitating the assembly of multimeric protein complexes inside the ER
  • central regulator of endoplasmic reticulum (ER) homeostasis, functioning in protein folding, ER calcium binding and modulation of transmembrane ER stress sensor activity
  • with TDGF1 bind at the cell surface to enhance tumor growth via the inhibition of TGF-beta signaling
  • may stabilize Raf-1 to maintain mitochondrial permeability and thus protect cells from endoplasmic reticulum stress-induced apoptosis
  • protects cells from cytotoxicity induced by DNA damage or endoplasmic reticulum (ER) stress
  • may stabilize RAF1 to maintain mitochondrial permeability and thus protect cells from ER stress-induced apoptosis
  • plays a central role in the prosurvival machinery, and its enhanced expression has been implicated in drug resistance, carcinogenesis, and metastasis
  • its expression affect the expression of voltage-dependent anion channel
  • at least under certain circumstances, the ER-resided chaperone HSPA5 can be retargeted to mitochondria and thereby may be involved in correlating unfolded protein response signaling between these two organelles
  • induced by TCR activation via a Ca2+-dependent pathway and may play a critical role in maintaining T cell viability in the steady and TCR-activated states
  • functions as a cell surface receptor in DMP1 endocytosis, caveolae mediate the intracellular transport of DMP1, and DMP1-containing vesicles are transported intracellularly to the Golgi and the nucleus via the microtubules
  • its induction is critical for control of protein folding and assembly, targeting of misfolded proteins for proteasome degradation, ER Ca2+ binding, and regulation of the activity of ER stress transducers
  • also acts as an apoptotic regulator by protecting cells against ER stress-induced cell death
  • essential for insulin biosynthesis, and enhancing chaperone capacity can improve beta-cell function in the presence of prolonged hyperglycemia
  • may be playing a role with PDIA2 in insulin biosynthesis, although an excess of PDIA2 disrupts normal proinsulin processing
  • with TDGF1, cooperatively regulate signaling via activin-A, activin-B, TGFB-1 and NODAL
  • necessary mediator of TDGF1 signaling in tumor, mammary epithelial and embryonic stem cells
  • necessary mediator of TDGF1 tumor growth factor activity because knockdown or antibody blockade of cell surface HSPA5 prevented TDGF1-dependent activation of PI3K/Akt and MAPK/ERK pathways
  • endoplasmic reticulum (ER) chaperone protein
  • essential role in protection from neuronal apoptosis
  • a role in misfolding of the islet betta-cell peptide human amylin
  • may critically regulate the function of the host vasculature within the tumor microenvironment
  • critical mediator of angiogenesis by regulating cell proliferation, survival, and migration
  • can decrease BCL2 sequestration by BIK at the endoplasmic reticulum, thus uncovering a potential new mechanism whereby GRP78 confers endocrine resistance in breast cancer
  • confers resistance to estrogen starvation-induced apoptosis in human breast cancer cells via a novel mechanism mediated by BIK
  • confers resistance to apoptosis induced by BIK and PMAIP1
  • a critical factor in SV40 infection
  • required for dislocation of SV40 from the endoplasmic reticulum to the cytosol
  • protein expressions of both HSP90B1 and HSPA5 are known to be induced by glucose deprivation
  • has an inhibitory effect on the aggregation of proteins containing expanded polyQ tract, may be an effective target for the treatment of polyQ diseases
  • having likely an inhibitory effect on the aggregation of proteins containing expanded polyQ tract
  • is involved in the control of ER homeostasis
  • TDGF1 and its cell-surface receptor HSPA5 are regulators of stem cell behavior in isolated fetal and adult mammary epithelial cells
  • HSP90AA1 and HSPA5 interact with PRDM14 and participate in cancer regulation
    • CELLULAR PROCESS protein, post translation, folding
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • forms a cell surface complex with TDGF1
  • ADAM7 forms complexes with calnexin (CANX), heat shock protein 5 (HSPA5), and integral membrane protein 2B (ITM2B)
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • human leukocyte antigen (HLA)-Cw3 alpha chains
  • Coagulation factor VIII, FVIII
  • Keratin polypeptides 8
  • endoplasmic reticulum protein 29, ERP29
  • alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors
  • transmembrane protein MTJ1
  • low density lipoprotein (LDL) receptor
  • Lymphoma proprotein convertase, LPC
  • mutant prion protein PrP Q217R (PrP(217))
  • haemagglutinin (H) and fusion (F) glycoproteins
  • pancreatic eIF2 kinase (PEK)
  • alpha(2)-Macroglobulin (alpha(2)M*)
  • mammalian BiP-associated protein, BAP
  • thyrotropin receptor, TSHR
  • apolipoprotein B-100 (apoB)
  • ER-resident protein ERdj5
  • GRP78-binding protein, GBP
  • large surface protein of hepatitis B virus
  • procaspase-7
  • interaction between LMAN2 and HSPA5, that is carbohydrate-independent
  • interacting with glycogen synthase kinase-3 (GSK3B), a promoter of ER stress-induced apoptosis, and HSPH1, (promotes ER stress-induced caspase-3 activation)
  • DNAJB9, DNAJC10 promote turnover of misfolded SFTPC and this activity is dependent on their ability to stimulate HSPA5 ATPase activity
  • UGGT1 is a potential HSPA5 activator and a cellular target for improvement of recombinant protein production using a cDNA screening system (pMID: 19466607)
  • misfolded human amylin oligomers
  • in retinal neurons, the molecular chaperone SIGMAR1 binds HSPA5 under stressful conditions
  • interaction of HSPA5 with BIK does not require its BH3 domain, which has been implicated in all previous BIK protein interactions
  • SIL1 facilitates the release of HSPA5 from unfolded protein substrates, enabling the subsequent folding and transport of the protein
  • in contrast to its mode of binding ATF6 and unfolded proteins, binds to ERN1 and EIF2AK3 in a different manner
  • HSPA5 is a dermokine-beta-associated protein (impairs ERK signaling through direct binding to HSPA5)
  • HSPA5 limits ER Ca(2+) leakage through the SEC61A1 complex by binding to the ER lumenal loop 7 of Sec61A1 in the vicinity of tyrosine 344
  • SERPINA12 binds to cell-surface HSPA5, which is recruited from ER to plasma membrane under ER stress
  • GPX7 is essential for releasing excessive ER stress by enhancing HSPA5 chaperone activity to maintain physiological homeostasis
  • dimerization of AGR2 attenuates ER stress-induced cell death through the association with HSPA5
  • RRBP1 may involve in the regulation of mRNA stability of UPR components including ATF6 and HSPA5
  • DNAJB11 is an abundant soluble endoplasmic reticulum (ER) co-chaperone of HSPA5, stimulating the ATPase activity of HSPA5 to increase HSPA5 affinity for client (or substrate) proteins
  • HSPA5 was a novel partner interacting with BAG3 (through direct interaction BAG3 could prevent the antiapoptotic effect of HSPA5 upon genotoxic stress)
  • upon interacting with SNCA, HSPA5 activates a signaling cascade leading to cofilin 1 inactivation and stabilization of microfilaments
  • DNAJC3 is a HSPA5 (immunoglobulin heavy-chain binding protein) co-chaperone
  • stabilization of WASF3 function occurs through its interaction with ATAD3A and HSPA5, which may provide a bridge between the ER and mitochondria, allowing communication between the two organelles
  • CRELD2 and MANF, are oppositely regulated by the overexpression of 78&
    • 8201;kDa glucose-regulated protein (HSPA5)
  • INPP5K interacts with PAK1 and glucose-regulated protein 78 (HSPA5), both of which are necessary for the regulation of insulin signaling
  • METTL21A is involved in Lys586 (Lys585) trimethylation of HSPA5
  • DNAJB11 is a co-factor of HSPA5, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins
  • HSPA5 protects ADAM17 against PDIAA6 catalyzed inactivation
  • turnover of HSPA5 was in part driven by its N-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway
  • KDELR2 competes with MV envelope proteins for binding to calnexin and HSPA5, and this interaction limits the availability of the chaperones for Measles Virus (MV) proteins, causing the reduction of virus spread and titers
  • OTUD3 interacts with, deubiquitylates and stabilizes the glucose-regulated protein HSPA5
    • cell & other
  • coreceptor for coxsackievirus A9 with MHC class 1 molecules which mediate virus internalization
    • REGULATION
    activated by PAWR (activates an extrinsic pathway involving cell surface HSPA5 for induction of apoptosis)
    induced by chronic hypoxia in human gastric tumor cells
    TCR activation via a Ca2+-dependent pathway
    repressed by E2F1 at the transcriptional level, through its DNA binding domain
    Other glucose regulated protein
    can be regulated by Ca2+ levels in the endoplasmic reticulum
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --other  
    expression correlates with histologic differentiation and favorable prognosis in neuroblastic tumors
    tumoral     --over  
    in various cancer cells and tumors, including breast, lung, liver, prostate, colon, and gastric cancers, correlating with malignancy, metastasis, and drug resistance
    tumoral     --over  
    in a variety of tumors and confers drug resistance in both proliferating and dormant cancer cells
    constitutional       gain of function
    with CASP12 were upregulated in cardiomyocytes in the diastolic heart failure resulting from hypertension
    constitutional     --over  
    suppresses apoptosis induced by BIK and PMAIP1, either alone or in combination
    constitutional     --low  
    in the cells expressing expanded polyQ tract-containing proteins
    Susceptibility to bipolar disorder
    Variant & Polymorphism other promotor polymorphisms may affect the interindividual variability of ER stress response and may confer a genetic risk factor for bipolar disorder
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    concomitant use of current chemotherapeutic agents and novel therapies against HSPA5 may offer a powerful dual approach to arrest cancer initiation, progression, and metastasis
    cancer  
    suppression HSPA5 through small interfering RNA sensitizes cancer cells to chemotherapeutic drug-mediated cell death and inhibits tumor progression and repression by E2F1 is one of the underlying mechanisms of E2F1-mediated sensitization of cancer cells
    cancer  
    disrupting the TDGF1/HSPA5 binding interface blocks oncogenic TDGF1 signaling and may have important therapeutic value in the treatment of cancer
    cancerhead and neck 
    regulation of the MUL1-HSPA5 axis can be a novel strategy for the treatment of HNC
    ANIMAL & CELL MODELS
    cytosolic ubiquitin staining is dramatically reduced in GRP78-null Purkinje cells. The mice show retarded growth and severe motor coordination defect by week 5 and cerebellar atrophy by week 13. A novel mouse model of accelerated cerebellar degeneration with basic and clinical applications