Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

HSPA5 (heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa))

Written2009-12Richard Zimmermann, Johanna Dudek
Medical Biochemistry, Molecular Biology, Saarland University, 66421 Homburg, Germany

(Note : for Links provided by Atlas : click)

Identity

Other namesBIP
BiP
FLJ26106
GRP78
MIF2
HGNC (Hugo) HSPA5
LocusID (NCBI) 3309
Atlas_Id 40876
Location 9q33.3  [Link to chromosome band 9q33]
Location_base_pair Starts at 127997127 and ends at 128003666 bp from pter ( according to hg19-Feb_2009)  [Mapping HSPA5.png]
Fusion genes
(updated 2016)
COL18A1 (21q22.3) / HSPA5 (9q33.3)CYB5D2 (17p13.2) / HSPA5 (9q33.3)HP1BP3 (1p36.12) / HSPA5 (9q33.3)
HSPA5 (9q33.3) / PPM1G (2p23.3)HSPA5 (9q33.3) / SF3A2 (19p13.3)NGFRAP1 () / HSPA5 (9q33.3)
STAT2 (12q13.3) / HSPA5 (9q33.3)UBL7 (15q24.1) / HSPA5 (9q33.3)

DNA/RNA

 
Description Starts at 127036953 bp and ends at 127043430 bp from pter.
Transcription The gene is constitutively expressed in all nucleated cells. Under cellular stress conditions (such as hypoxia or glucose starvation) transcritption is upregulated via the "unfolded protein response" (UPR).
Pseudogene Four pseudogenes were reported (human pseudogenes from protein P11021).

Protein

Note HspA5 (heat shock protein A5), also termed immunoglobulin heavy chain binding protein (BiP) or glucose regulated protein with an apparent mass of 78 kDa (Grp78) is a Hsp70-type molecular chaperone of the endoplasmic reticulum (ER).
Description The protein is synthesized as a precursor with an aminoterminal signal peptide of 18 amino acid residues that directs the precursor into the ER. The mature protein (i.e. after removal of the signal peptide by signal peptidase in the ER) contains 635 amino acid residues, including a carboxyterminal ER retention motif that comprises four amino acid residues (KDEL).
Expression The HSPA5 gene is expressed in all nucleated cells, in particular in thyroid-, lung-, smooth muscle-, liver-, and various cells of the immune system. Under cellular stress conditions the gene is over-expressed due to UPR.
 
  Central role of HspA5/BiP in gene expression and calcium homeostasis. Typically, BiP is involved in protein transport into and in protein folding and assembly in the ER. Upon protein misfolding -either due to mutation in a client protein or to environmental conditions, such as hypoxia or glucose starvation- one or more proteins start to aggregate and therefore, sequester BiP. This removes BiP from its normal tasks as well as from the signaling molecules in the ER membrane (ATF6, IRE1, PERK). Subsequently, the unfolded protein response/UPR is activated and leads to a reduction of global protein synthesis and the over-production of ER chaperones and ERAD components (ERAD, ER associated protein degradation). If this response fails apoptosis is induced.
Localisation HspA5/BiP is a resident protein of the endoplasmic reticulum (ER). Typically, it is a soluble protein of the lumen of the ER. However, a subfraction of HspA5/BiP can be found on the cell surface of certain cell types, in particular of cancer cells.
 
  Interactome of HspA5/BiP. Calcium binding proteins are labeled with red asterisk, membrane proteins are shown in green. ERj, ER protein with j-domain; PDI, protein disulfide isomerase; Grp, glucose regulated protein.
Function The ER is involved in a variety of essential and interconnected processes, including protein biogenesis (protein transport into the ER, protein folding and assembly, and ER associated protein degradation), signal transduction (unfolded protein response/UPR), and calcium homeostasis. The central player in all these processes is the molecular chaperone HspA5/BiP. HspA5/BiP crucially depends on a number of interaction partners, including co-chaperones (ERj1 through ERj7), nucleotide exchange factors (Sil1, Grp170), other chaperones (calnexin, calreticulin, Grp94, UGGT), folding catalysts (protein disulfide isomerases/PDI, and peptidyl prolyl cis/trans isomerases such as Cyclophilin B) and signaling molecules (IRE1, ATF6, PERK, Sigma-1 receptor).
As a typical Hsp70, HspA5/BiP comprises an aminoterminal nucleotide binding domain and a carboxyterminal substrate (poly)peptide binding domain. Its functional cycle involves an ATP-form with low affinity for substrate (poly)peptides and an ADP-form with high substrate affinity and is regulated by Hsp40-type co-chaperones and nucleotide exchange factors.
Molecular chaperones of the Hsp70 type family reversibly bind to substrate polypeptides via the substrate binding domain (SBD). Typically, Hsp70 substrates are hydrophobic oligopeptides within more or less unfolded polypeptides. The binding of a substrate to the SBD inhibits unproductive interactions of the polypeptide and favors productive folding and assembly that occur concomitant with release from Hsp70. In addition, Hsp70s can regulate the activities of folded polypeptides.
 
  Functional cycle of BiP. An unfolded substrate (poly)peptide is shown in red. ADP, adenosine diphosphate; ATP, adenosine triphosphate; NBD, nucleotide binding domain; NEF, nucleotide exchange factor; Pi, inorganic phosphate; SBD, substrate binding domain with lid.
Homology HspA5/BiP belongs to the heat shock protein 70 (Hsp70) family of molecular chaperones. As such it is structurally related to the cytosolic Hsp70s (Hsc70, Hsp70.1, Hsp70.3, Hsp70L1) and the mitochondrial Hsp70 (Grp75/mtHsp75). In addition, HspA5/BiP is structurally related to its nucleotide exchange factor Grp170 that also belongs to the Hsp70 protein family.

Mutations

Germinal Not known.
Somatic Not known.

Implicated in

Note
Entity Various cancers such as astrocytoma, breast cancer, glioblastoma, liver cancer, lung cancer, and prostate cancer
Note HspA5/BiP has been linked to various cancers. Due to poor vascularization and the resulting hypoxia and glucose starvation, tumor cells are prone to ER stress and therefore, UPR. In cultured cells, HspA5/BiP is one of the proteins involved in protecting cancer cells against ER stress-induced apoptosis.
Disease HSPA5/BIP expression is highly upregulated in a variety of cancer tissues due to UPR. The HspA5/BiP protects cancer cells against apoptosis through various mechanisms : i) it fights protein aggegation in the ER, ii) due to its ability to bind Ca2+ it prevents calcium signaling in the cytosol, iii) it prevents the activation of pro-apoptotic components, such as BIK, BAX, pro-caspase 7 and pro-caspase 12. Furthermore, HspA5/BiP protects cancer cells against various chemotherapeutic agents that target the same pro-apoptotic components.
  
Entity Haemolytic uraemic syndrome (HUS)
Note HspA5/BiP has been linked to a group of infectious diseases that are caused by Shigella toxin producing E. coli (such as HUS).
Disease Shiga toxigenic Escherichia coli (STEC) strains cause morbidity and mortality. Some of these pathogens produce Shiga toxin and AB5 toxin and are responsible for gastrointestinal diseases, such as HUS. During an infection, the bacterial cytotoxin enters human cells by endocytosis and retrograde transport to the ER. In the ER, BiP is the major target of the catalytic A-subunit, which inactivates BiP by limited proteolysis. Finally, all BiP functions are completely lost, and the affected cells die.
  
Entity Marinesco-Sjogren syndrome (MSS)
Note HspA5/BiP has indirectly been linked to a hereditary disease that is caused by a lack of function of the nucleotide exchange factor of BiP, termed Sil1.
  

Bibliography

Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands.
Arap MA, Lahdenranta J, Mintz PJ, Hajitou A, Sarkis AS, Arap W, Pasqualini R.
Cancer Cell. 2004 Sep;6(3):275-84.
PMID 15380518
 
Visiting the ER: the endoplasmic reticulum as a target for therapeutics in traffic related diseases.
Aridor M.
Adv Drug Deliv Rev. 2007 Aug 10;59(8):759-81. Epub 2007 Jun 21. (REVIEW)
PMID 17681635
 
Posttranslational association of immunoglobulin heavy chain binding protein with nascent heavy chains in nonsecreting and secreting hybridomas.
Bole DG, Hendershot LM, Kearney JF.
J Cell Biol. 1986 May;102(5):1558-66.
PMID 3084497
 
Calcium signaling.
Clapham DE.
Cell. 2007 Dec 14;131(6):1047-58. (REVIEW)
PMID 18083096
 
Functions and pathologies of BiP and its interaction partners.
Dudek J, Benedix J, Cappel S, Greiner M, Jalal C, Muller L, Zimmermann R.
Cell Mol Life Sci. 2009 May;66(9):1556-69. (REVIEW)
PMID 19151922
 
GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis.
Fu Y, Li J, Lee AS.
Cancer Res. 2007 Apr 15;67(8):3734-40.
PMID 17440086
 
Immunoglobulin heavy chain binding protein.
Haas IG, Wabl M.
Nature. 1983 Nov 24-30;306(5941):387-9.
PMID 6417546
 
A new role for BiP: closing the aqueous translocon pore during protein integration into the ER membrane.
Haigh NG, Johnson AE.
J Cell Biol. 2002 Jan 21;156(2):261-70. Epub 2002 Jan 21.
PMID 11807091
 
Interaction of BiP with newly synthesized immunoglobulin light chain molecules: cycles of sequential binding and release.
Knittler MR, Haas IG.
EMBO J. 1992 Apr;11(4):1573-81.
PMID 1563355
 
Molecular chaperones: multiple functions, pathologies, and potential applications.
Macario AJ, Conway de Macario E.
Front Biosci. 2007 Jan 1;12:2588-600. (REVIEW)
PMID 17127265
 
ER chaperones in mammalian development and human diseases.
Ni M, Lee AS.
FEBS Lett. 2007 Jul 31;581(19):3641-51. Epub 2007 Apr 25. (REVIEW)
PMID 17481612
 
AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP.
Paton AW, Beddoe T, Thorpe CM, Whisstock JC, Wilce MC, Rossjohn J, Talbot UM, Paton JC.
Nature. 2006 Oct 5;443(7111):548-52.
PMID 17024087
 
Endoplasmic reticulum-associated degradation.
Romisch K.
Annu Rev Cell Dev Biol. 2005;21:435-56. (REVIEW)
PMID 16212502
 
Polypeptide-binding proteins mediate completion of co-translational protein translocation into the mammalian endoplasmic reticulum.
Tyedmers J, Lerner M, Wiedmann M, Volkmer J, Zimmermann R.
EMBO Rep. 2003 May;4(5):505-10.
PMID 12704426
 
Signaling the unfolded protein response from the endoplasmic reticulum.
Zhang K, Kaufman RJ.
J Biol Chem. 2004 Jun 18;279(25):25935-8. Epub 2004 Apr 7. (REVIEW)
PMID 15070890
 

Citation

This paper should be referenced as such :
Zimmermann, R ; Dudek, J
HSPA5 (heat shock 70kDa protein 5 (glucose-regulated protein, 78kDa))
Atlas Genet Cytogenet Oncol Haematol. 2010;14(9):881-884.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/HSPA5ID40876ch9q33.html


External links

Nomenclature
HGNC (Hugo)HSPA5   5238
Cards
AtlasHSPA5ID40876ch9q33
Entrez_Gene (NCBI)HSPA5  3309  heat shock protein family A (Hsp70) member 5
AliasesBIP; GRP78; HEL-S-89n; MIF2
GeneCards (Weizmann)HSPA5
Ensembl hg19 (Hinxton)ENSG00000044574 [Gene_View]  chr9:127997127-128003666 [Contig_View]  HSPA5 [Vega]
Ensembl hg38 (Hinxton)ENSG00000044574 [Gene_View]  chr9:127997127-128003666 [Contig_View]  HSPA5 [Vega]
ICGC DataPortalENSG00000044574
TCGA cBioPortalHSPA5
AceView (NCBI)HSPA5
Genatlas (Paris)HSPA5
WikiGenes3309
SOURCE (Princeton)HSPA5
Genomic and cartography
GoldenPath hg19 (UCSC)HSPA5  -     chr9:127997127-128003666 -  9q33.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)HSPA5  -     9q33.3   [Description]    (hg38-Dec_2013)
EnsemblHSPA5 - 9q33.3 [CytoView hg19]  HSPA5 - 9q33.3 [CytoView hg38]
Mapping of homologs : NCBIHSPA5 [Mapview hg19]  HSPA5 [Mapview hg38]
OMIM138120   
Gene and transcription
Genbank (Entrez)AA433933 AF188611 AF216292 AJ271729 AK129617
RefSeq transcript (Entrez)NM_005347
RefSeq genomic (Entrez)NC_000009 NC_018920 NG_027761 NT_008470 NW_004929366
Consensus coding sequences : CCDS (NCBI)HSPA5
Cluster EST : UnigeneHs.743241 [ NCBI ]
CGAP (NCI)Hs.743241
Alternative Splicing GalleryENSG00000044574
Gene ExpressionHSPA5 [ NCBI-GEO ]   HSPA5 [ EBI - ARRAY_EXPRESS ]   HSPA5 [ SEEK ]   HSPA5 [ MEM ]
Gene Expression Viewer (FireBrowse)HSPA5 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3309
GTEX Portal (Tissue expression)HSPA5
Protein : pattern, domain, 3D structure
UniProt/SwissProtP11021 (Uniprot)
NextProtP11021  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP11021
Splice isoforms : SwissVarP11021 (Swissvar)
PhosPhoSitePlusP11021
Domaine pattern : Prosite (Expaxy)ER_TARGET (PS00014)    HSP70_1 (PS00297)    HSP70_2 (PS00329)    HSP70_3 (PS01036)   
Domains : Interpro (EBI)Heat_shock_70_CS    HSP70_C    HSP70_peptide-bd    Hsp_70_fam   
Domain families : Pfam (Sanger)HSP70 (PF00012)   
Domain families : Pfam (NCBI)pfam00012   
DMDM Disease mutations3309
Blocks (Seattle)HSPA5
PDB (SRS)3IUC    3LDL    3LDN    3LDO    3LDP    5E84    5E85    5E86   
PDB (PDBSum)3IUC    3LDL    3LDN    3LDO    3LDP    5E84    5E85    5E86   
PDB (IMB)3IUC    3LDL    3LDN    3LDO    3LDP    5E84    5E85    5E86   
PDB (RSDB)3IUC    3LDL    3LDN    3LDO    3LDP    5E84    5E85    5E86   
Structural Biology KnowledgeBase3IUC    3LDL    3LDN    3LDO    3LDP    5E84    5E85    5E86   
SCOP (Structural Classification of Proteins)3IUC    3LDL    3LDN    3LDO    3LDP    5E84    5E85    5E86   
CATH (Classification of proteins structures)3IUC    3LDL    3LDN    3LDO    3LDP    5E84    5E85    5E86   
SuperfamilyP11021
Human Protein AtlasENSG00000044574
Peptide AtlasP11021
HPRD00682
IPIIPI00003362   IPI01014129   
Protein Interaction databases
DIP (DOE-UCLA)P11021
IntAct (EBI)P11021
FunCoupENSG00000044574
BioGRIDHSPA5
STRING (EMBL)HSPA5
ZODIACHSPA5
Ontologies - Pathways
QuickGOP11021
Ontology : AmiGOglycoprotein binding  calcium ion binding  protein binding  ATP binding  nucleus  nucleus  mitochondrion  endoplasmic reticulum  endoplasmic reticulum  endoplasmic reticulum  endoplasmic reticulum lumen  endoplasmic reticulum membrane  smooth endoplasmic reticulum  endoplasmic reticulum-Golgi intermediate compartment  plasma membrane  focal adhesion  ER overload response  activation of signaling protein activity involved in unfolded protein response  COP9 signalosome  cell surface  membrane  ATPase activity  ATPase activity  enzyme binding  protein domain specific binding  cerebellum structural organization  cerebellar Purkinje cell layer development  substantia nigra development  integral component of endoplasmic reticulum membrane  positive regulation of cell migration  ER-associated ubiquitin-dependent protein catabolic process  midbody  negative regulation of transforming growth factor beta receptor signaling pathway  endoplasmic reticulum unfolded protein response  positive regulation of protein ubiquitination  ubiquitin protein ligase binding  endoplasmic reticulum chaperone complex  protein folding in endoplasmic reticulum  maintenance of protein localization in endoplasmic reticulum  IRE1-mediated unfolded protein response  PERK-mediated unfolded protein response  ATF6-mediated unfolded protein response  cellular response to glucose starvation  melanosome  ribosome binding  negative regulation of apoptotic process  negative regulation of apoptotic process  myelin sheath  unfolded protein binding  chaperone binding  misfolded protein binding  regulation of protein folding in endoplasmic reticulum  extracellular exosome  cellular response to antibiotic  cellular response to manganese ion  cellular response to interleukin-4  negative regulation of protein homodimerization activity  toxin transport  regulation of ATF6-mediated unfolded protein response  regulation of IRE1-mediated unfolded protein response  regulation of PERK-mediated unfolded protein response  positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress  
Ontology : EGO-EBIglycoprotein binding  calcium ion binding  protein binding  ATP binding  nucleus  nucleus  mitochondrion  endoplasmic reticulum  endoplasmic reticulum  endoplasmic reticulum  endoplasmic reticulum lumen  endoplasmic reticulum membrane  smooth endoplasmic reticulum  endoplasmic reticulum-Golgi intermediate compartment  plasma membrane  focal adhesion  ER overload response  activation of signaling protein activity involved in unfolded protein response  COP9 signalosome  cell surface  membrane  ATPase activity  ATPase activity  enzyme binding  protein domain specific binding  cerebellum structural organization  cerebellar Purkinje cell layer development  substantia nigra development  integral component of endoplasmic reticulum membrane  positive regulation of cell migration  ER-associated ubiquitin-dependent protein catabolic process  midbody  negative regulation of transforming growth factor beta receptor signaling pathway  endoplasmic reticulum unfolded protein response  positive regulation of protein ubiquitination  ubiquitin protein ligase binding  endoplasmic reticulum chaperone complex  protein folding in endoplasmic reticulum  maintenance of protein localization in endoplasmic reticulum  IRE1-mediated unfolded protein response  PERK-mediated unfolded protein response  ATF6-mediated unfolded protein response  cellular response to glucose starvation  melanosome  ribosome binding  negative regulation of apoptotic process  negative regulation of apoptotic process  myelin sheath  unfolded protein binding  chaperone binding  misfolded protein binding  regulation of protein folding in endoplasmic reticulum  extracellular exosome  cellular response to antibiotic  cellular response to manganese ion  cellular response to interleukin-4  negative regulation of protein homodimerization activity  toxin transport  regulation of ATF6-mediated unfolded protein response  regulation of IRE1-mediated unfolded protein response  regulation of PERK-mediated unfolded protein response  positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress  
Pathways : BIOCARTAStathmin and breast cancer resistance to antimicrotubule agents [Genes]    Prion Pathway [Genes]   
Pathways : KEGGProtein export    Protein processing in endoplasmic reticulum    Antigen processing and presentation    Thyroid hormone synthesis    Prion diseases   
REACTOMEP11021 [protein]
REACTOME PathwaysR-HSA-381070 IRE1alpha activates chaperones [pathway]
REACTOME PathwaysR-HSA-114608 Platelet degranulation [pathway]
REACTOME PathwaysR-HSA-3371453 Regulation of HSF1-mediated heat shock response [pathway]
REACTOME PathwaysR-HSA-983170 Antigen Presentation: Folding, assembly and peptide loading of class I MHC [pathway]
REACTOME PathwaysR-HSA-381042 PERK regulates gene expression [pathway]
REACTOME PathwaysR-HSA-381183 ATF6-alpha activates chaperone genes [pathway]
REACTOME PathwaysR-HSA-381033 ATF6-alpha activates chaperones [pathway]
NDEx Network
Atlas of Cancer Signalling NetworkHSPA5
Wikipedia pathwaysHSPA5
Orthology - Evolution
OrthoDB3309
GeneTree (enSembl)ENSG00000044574
Phylogenetic Trees/Animal Genes : TreeFamHSPA5
Homologs : HomoloGeneHSPA5
Homology/Alignments : Family Browser (UCSC)HSPA5
Gene fusions - Rearrangements
Fusion : MitelmanCOL18A1/HSPA5 [21q22.3/9q33.3]  [t(9;21)(q33;q22)]  
Fusion: TCGACOL18A1 21q22.3 HSPA5 9q33.3 HNSC
Polymorphisms : SNP, variants
NCBI Variation ViewerHSPA5 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)HSPA5
dbVarHSPA5
ClinVarHSPA5
1000_GenomesHSPA5 
Exome Variant ServerHSPA5
ExAC (Exome Aggregation Consortium)HSPA5 (select the gene name)
Genetic variants : HAPMAP3309
Genomic Variants (DGV)HSPA5 [DGVbeta]
Mutations
ICGC Data PortalHSPA5 
TCGA Data PortalHSPA5 
Broad Tumor PortalHSPA5
OASIS PortalHSPA5 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICHSPA5 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch HSPA5
DgiDB (Drug Gene Interaction Database)HSPA5
DoCM (Curated mutations)HSPA5 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)HSPA5 (select a term)
intoGenHSPA5
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)9:127997127-128003666  ENSG00000044574
CONAN: Copy Number AnalysisHSPA5 
Mutations and Diseases : HGMDHSPA5
OMIM138120   
MedgenHSPA5
Genetic Testing Registry HSPA5
NextProtP11021 [Medical]
TSGene3309
GENETestsHSPA5
Huge Navigator HSPA5 [HugePedia]
snp3D : Map Gene to Disease3309
BioCentury BCIQHSPA5
ClinGenHSPA5
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3309
Chemical/Pharm GKB GenePA29504
Clinical trialHSPA5
Miscellaneous
canSAR (ICR)HSPA5 (select the gene name)
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineHSPA5
EVEXHSPA5
GoPubMedHSPA5
iHOPHSPA5
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Aug 10 19:00:58 CEST 2016

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.