Biomarker: HSPA5

Histology type: endometrial carcinoma

Stage: high risk

Country: China

Region: Shanghai 

Followed up time :

Subgroup 1 name : positive

Subgroup 1 number: 77

Subgroup 2 name: negative

Subgroup 2 number: 42

Conclusion: HSPA5 may play an important role in the progression of EC. It is potential biomarkers to better predict high-risk EC and thereby guide clinical therapy.

Sample type : tissue

Sample method: two-dimensional gel electrophoresis (2-DE)/liquid chromatography electrospray ionization tandem mass spectrometry (LC–ESI–MS/MS)

Expression pattern : positive expression

Expression elevation: For semiquantitative assessment of the immunohistochemical results, the mean percentage of positive tumor cells was determined in at least 10 random fields at ×400 magnification in each section and graded as focal (≤10%), regional (11%–50%), or diffuse (>50%). The intensity of the PKM2 and HSPA5 immunoreaction was graded weak, moderate, or intense. The mean percentage of positive tumor cells and the staining intensity were then combined to produce an IHC result. Cases that graded ‘intense diffuse, intense regional, moderate diffuse, and moderate regional’ were considered positive; others were considered negative.

Statictics: cutoff<50;cutoff>50

Cohort age: 16;103

Subgroup 1 age: 11;66

Subgroup 2 age: 5;37

Funtion Uniprot: Endoplasmic reticulum chaperone that plays a key role in protein folding and quality control in the endoplasmic reticulum lumen (PubMed:2294010, PubMed:23769672, PubMed:23990668, PubMed:28332555). Involved in the correct folding of proteins and degradation of misfolded proteins via its interaction with DNAJC10/ERdj5, probably to facilitate the release of DNAJC10/ERdj5 from its substrate (By similarity). Acts as a key repressor of the ERN1/IRE1-mediated unfolded protein response (UPR) (PubMed:1550958, PubMed:19538957). In the unstressed endoplasmic reticulum, recruited by DNAJB9/ERdj4 to the luminal region of ERN1/IRE1, leading to disrupt the dimerization of ERN1/IRE1, thereby inactivating ERN1/IRE1 (By similarity). Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP from ERN1/IRE1, allowing homodimerization and subsequent activation of ERN1/IRE1 (By similarity). Plays an auxiliary role in post-translational transport of small presecretory proteins across endoplasmic reticulum (ER). May function as an allosteric modulator for SEC61 channel-forming translocon complex, likely cooperating with SEC62 to enable the productive insertion of these precursors into SEC61 channel. Appears to specifically regulate translocation of precursors having inhibitory residues in their mature region that weaken channel gating. May also play a role in apoptosis and cell proliferation (PubMed:26045166).By Similarity8 Publications (Microbial infection) Plays an important role in viral binding to the host cell membrane and entry for several flaviruses such as Dengue virus, Zika virus and Japanese encephalitis virus (PubMed:33432092, PubMed:15098107, PubMed:28053106). Acts as a component of the cellular receptor for Dengue virus serotype 2/DENV-2 on human liver cells (PubMed:15098107).3 Publications (Microbial infection) Acts as a receptor for CotH proteins expressed by fungi of the order mucorales, the causative agent of mucormycosis, which plays an important role in epithelial cell invasion by the fungi (PubMed:24355926, PubMed:20484814, PubMed:32487760). Acts as a receptor for R.delemar CotH3 in nasal epithelial cells, which may be an early step in rhinoorbital/cerebral mucormycosis (RCM) disease progression (PubMed:32487760).3 Publications

UniProt ID: P11021

UniProt Link: https://www.uniprot.org/uniprotkb/P11021/entry

Biological function from UniProt: #Host-virus interaction

Molecular function from UniProt:

Subcellular UniProt: #Cytoplasm #Endoplasmic reticulum

Alternative name from UniProt:

Caution: AMPylation was initially reported to take place at Ser-365 and Thr-366 in vitro, and promote activation of HSPA5/BiP (PubMed:25601083). However, it was later shown that AMPylation takes place at Thr-518 and leads to inactivation of HSPA5/BiP

Miscellaneous: Antibodies against the protein protects endothelial cells from invasion by the fungus R.delemar, a causative agent of mucormycosis, and could thus potentially be used to treat mucormycosis disease (PubMed:20484814). Antibodies against the protein also protect a diabetic ketoacidosis mouse model against mucormycosis (PubMed:20484814).

Catalytic activity: ATP + H2O = ADP + H+ + phosphate

Activity regulation: The chaperone activity is regulated by ATP-induced allosteric coupling of the nucleotide-binding (NBD) and substrate-binding (SBD) domains. In the ADP-bound and nucleotide-free (apo) states, the two domains have little interaction (PubMed:26655470). In contrast, in the ATP-bound state the two domains are tightly coupled, which results in drastically accelerated kinetics in both binding and release of polypeptide substrates (PubMed:26655470). J domain-containing co-chaperones (DNAJB9/ERdj4 or DNAJC10/ERdj5) stimulate the ATPase activity and are required for efficient substrate recognition by HSPA5/BiP (By similarity). Homooligomerization inactivates participating HSPA5/BiP protomers and probably act as reservoirs to store HSPA5/BiP molecules when they are not needed by the cell (By similarity).

Recommended name: Endoplasmic reticulum chaperone BiP

Gene name from HGNC: HSPA5 (BiP, GRP78)

HPA class: Disease related genes Enzymes Plasma proteins Potential drug targets Transporters

AlphaFold DB: P11021

AlphaFold Link: https://alphafold.ebi.ac.uk/entry/P11021

Induction: By endoplasmic reticulum stress (PubMed:21289099). Induced in nasal epithelial cells by high free iron levels (PubMed:32487760, PubMed:20484814, PubMed:27159390). Induced in nasal epithelial cells in high glucose (PubMed:32487760, PubMed:20484814, PubMed:27159390). Induced in nasal epithelial cells by 3-hydroxybutyric acid (BHB) (PubMed:32487760, PubMed:27159390).

HPA link: https://www.proteinatlas.org/ENSG00000044574-HSPA5

Tissue specificity RNA from HPA: Low tissue specificity

Tissue expression from HPA: Ubiquitous cytoplasmic expression, highly abundant in immune, neuronal cells and thyroid follicular cells.

Single cell type specificity Cell type enhanced (Syncytiotrophoblasts)

Immune cell specificity: Low immune cell specificity

Cancer prognostic summary HPA Prognostic marker in renal cancer (unfavorable)

Pathology link: https://www.proteinatlas.org/ENSG00000044574-HSPA5/pathology

Pathology endo: https://www.proteinatlas.org/ENSG00000044574-HSPA5/pathology/endometrial+cancer

Note1: Autoantigen in rheumatoid arthritis

OMIM: 138120

OMIM link2: https://www.omim.org/entry/138120

HGNC ID: HGNC:5238

HGNC link: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:5238