HSPH1

Summary

HSPH1 (heat shock protein family H (Hsp110) member 1, HGNC:16969) is a protein-coding gene on chromosome 13q12.3, encoding Heat shock protein 105 kDa (Q92598). Acts as a nucleotide-exchange factor (NEF) for chaperone proteins HSPA1A and HSPA1B, promoting the release of ADP from HSPA1A/B thereby triggering client/substrate protein release. In precision oncology, HSPH1 T17 DELETION confers sensitivity to Fluorouracil + Oxaliplatin in Colorectal Cancer (CIViC Level B); 1 further curated variant–drug associations are listed below.

This gene encodes a member of the heat shock protein 70 family of proteins. The encoded protein functions as a nucleotide exchange factor for the molecular chaperone heat shock cognate 71 kDa protein (Hsc70). In addition, this protein plays a distinct but related role as a holdase that inhibits the aggregation of misfolded proteins, including the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Elevated expression of this protein has been observed in numerous human cancers.

Source: NCBI Gene 10808 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 128 total
• Druggable target: yes
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• MANE Select transcript: NM_006644

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16969
Approved symbol	HSPH1
Name	heat shock protein family H (Hsp110) member 1
Location	13q12.3
Locus type	gene with protein product
Status	Approved
Aliases	HSP105B, KIAA0201, HSP105A, NY-CO-25
Ensembl gene	ENSG00000120694
Ensembl biotype	protein_coding
OMIM	610703
Entrez	10808

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 14 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000320027, ENST00000380405, ENST00000435381, ENST00000445273, ENST00000469538, ENST00000602786, ENST00000626866, ENST00000629751, ENST00000630972, ENST00000853999, ENST00000936549, ENST00000936550, ENST00000936551, ENST00000954002, ENST00000954003, ENST00000954004, ENST00000954005, ENST00000954006

RefSeq mRNA: 5 — MANE Select: NM_006644 NM_001286503, NM_001286504, NM_001286505, NM_001349704, NM_006644

CCDS: CCDS66525, CCDS66526, CCDS73559, CCDS9340

Canonical transcript exons

ENST00000320027 — 18 exons

Exon	Start	End
ENSE00002258401	31134973	31137524
ENSE00003477120	31139000	31139107
ENSE00003491535	31149954	31150182
ENSE00003506577	31145563	31145768
ENSE00003553548	31147959	31148092
ENSE00003569009	31154633	31154755
ENSE00003573204	31148374	31148480
ENSE00003574804	31152852	31152951
ENSE00003609243	31141122	31141259
ENSE00003624229	31155514	31155654
ENSE00003637546	31158806	31158863
ENSE00003647845	31138407	31138568
ENSE00003652887	31150947	31151191
ENSE00003668822	31140184	31140309
ENSE00003669135	31143792	31143923
ENSE00003672993	31151609	31151742
ENSE00003686920	31138781	31138900
ENSE00003896099	31161476	31161904

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 67.1932 / max 4905.0337, expressed in 1804 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136688	40.0354	1787
136689	14.4301	1734
136687	6.4162	1598
136691	4.4008	1547
136690	1.0207	595
136692	0.6398	378
136675	0.1397	43
136693	0.0811	23
136686	0.0295	9

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.30	gold quality
bronchial epithelial cell	CL:0002328	99.29	gold quality
epithelium of bronchus	UBERON:0002031	98.86	gold quality
bronchus	UBERON:0002185	98.70	gold quality
nucleus accumbens	UBERON:0001882	98.48	gold quality
postcentral gyrus	UBERON:0002581	98.32	gold quality
caudate nucleus	UBERON:0001873	98.22	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.20	gold quality
putamen	UBERON:0001874	98.18	gold quality
CA1 field of hippocampus	UBERON:0003881	98.15	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.09	gold quality
parietal lobe	UBERON:0001872	97.97	gold quality
superior frontal gyrus	UBERON:0002661	97.97	gold quality
choroid plexus epithelium	UBERON:0003911	97.95	gold quality
right frontal lobe	UBERON:0002810	97.94	gold quality
ventricular zone	UBERON:0003053	97.91	gold quality
middle temporal gyrus	UBERON:0002771	97.86	gold quality
entorhinal cortex	UBERON:0002728	97.78	gold quality
hypothalamus	UBERON:0001898	97.65	gold quality
orbitofrontal cortex	UBERON:0004167	97.51	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	97.47	gold quality
Ammon’s horn	UBERON:0001954	97.44	gold quality
right uterine tube	UBERON:0001302	97.35	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.34	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.34	gold quality
amygdala	UBERON:0001876	97.30	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.23	gold quality
temporal lobe	UBERON:0001871	97.02	gold quality
telencephalon	UBERON:0001893	97.01	gold quality
adenohypophysis	UBERON:0002196	97.01	gold quality

Single-cell (SCXA)

Detected in 20 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	7061.03
E-CURD-79	yes	4941.33
E-MTAB-6678	yes	3089.78
E-MTAB-9067	yes	1515.28
E-CURD-10	yes	1191.82
E-HCAD-1	yes	37.77
E-CURD-122	yes	31.60
E-GEOD-135922	yes	25.13
E-CURD-114	yes	11.80
E-GEOD-130148	yes	7.15
E-HCAD-10	yes	7.07
E-GEOD-81547	yes	4.78
E-CURD-97	no	7598.63
E-MTAB-10137	no	3195.07
E-CURD-89	no	3050.01

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
HSPA1A	Activation
HSPA1B	Activation

Upstream regulators (CollecTRI, top): FOS, MYC, ONECUT1

miRNA regulators (miRDB)

151 targeting HSPH1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515

Literature-anchored findings (GeneRIF, showing 28)

• Heat shock protein 105 is overexpressed in a variety of human tumors (PMID:14534695)
• HSP105 appears to chaperone the responses to endoplasmic reticulum (ER) stress through its interactions with GRP78 and GSK3, and without HSP105 cell death following ER stress proceeds by a non-caspase-3-dependent process. (PMID:18083346)
• HSP105 analysis may be a helpful tool as a poor prognostic indicator and as a diagnostic aid in problematic lesions. (PMID:18477890)
• HSP 105 is thought to be a more relevant tumor-associated antigen in malignant melanoma than is HSP 70. (PMID:19476517)
• Hsp105alpha and Hsp105beta suppressed the expanded polyQ tract-induced protein aggregation and apoptosis through the induction of Hsp70. (PMID:20542028)
• A direct correlation between HSP105 expression and lymphoma aggressiveness was also apparent. (PMID:21860023)
• The Hsp105-mediated multilevel regulation of DeltaF508 CFTR folding and quality control provides new opportunities to understand how chaperone machinery regulates the homeostasis and functional expression of misfolded proteins in the cell. (PMID:22505710)
• It restricts aggregation of denaturated proteins,plays a role in protein folding in cytoplasms,and enhance expression of hsp70 in cell nucleus.(review) (PMID:22712230)
• High HSP105 expression is associated with Barrett’s esophagus. (PMID:22901192)
• HSPH1 and HSPH2 are bona fide chaperones on their own that collaborate with DNAJA1 and DNAJB1 to hydrolyze ATP and unfold polypeptides and HSPA1A and HSPH1 formed a powerful molecular machinery. (PMID:23737532)
• A receiver operating characteristic curve constructed with HSP105 and TIM gave a sensitivity of 54.3% and 95% (38/40) specificity in discriminating esophageal squamous cell carcinoma from matched controls. (PMID:24157810)
• we measured the binding of human Hsp72 (HSPA1A) to BAG1, BAG2, BAG3, and the unrelated NEF Hsp105. These studies revealed a clear hierarchy of affinities: BAG3 > BAG1 > Hsp105 » BAG2. (PMID:24318877)
• About 25% of patients with stages II-III colorectal tumors with microsatellite instability have an excellent response to chemotherapy, due to large, biallelic deletions in the T(17) intron repeat of HSP110 in tumor DNA. (PMID:24512910)
• HSP105 depletion disrupts the integration of protein phosphatase 2A into the beta-catenin degradation complex, favoring the hyperphosphorylation and degradation of beta-catenin. (PMID:25645927)
• HSP110 HT17 alone correctly classified samples judged to be uncertain with the pentaplex panel. (PMID:26831756)
• the expression of HSP110 in colon cancer contributes to STAT3-dependent tumor growth (PMID:27819670)
• Hsp105alpha localizes to the nucleus, interacts with HIF-1alpha and induces HIF-1a accumulation in CoCl2-treated cells. (PMID:28185835)
• deletion of the HSP110 T17 repeat was frequently observed in microsatellite-unstable advanced gastric cancers. (PMID:28811251)
• Established heat shock protein 110 (HSP110) as a prognostic biomarker of colorectal carcinomas (CRCs) with microsatellite instability-high (MSI-H) by considering the intratumoral heterogeneity of HSP110 expression. The HSP110wt-low MSI-H CRCs were significantly correlated with larger deletions in the HSP110 T17 mononucleotide repeat (>/=4 bp; p < 0.001). (PMID:28971530)
• expression not an independent prognostic factor in gastric cancer patients with peritoneal metastasis, but might be a new marker of chemosensitivity (PMID:29204054)
• High HSP110 is associated with B-cell diffuse large B-cell lymphoma through regulating NF-kappaB signaling and MyD88 stabilization. (PMID:29871863)
• Hsp105 is required for the activation of spindle assembly checkpoint under heat shock-induced mitotic arrest. (PMID:30496702)
• HSP110 through its interaction with the Ku70/80 heterodimer may participate in DNA repair. (PMID:30542121)
• HSP105 expression in oral squamous cell carcinoma: Correlation with clinicopathological features and outcomes. (PMID:32128880)
• Oncogene HSPH1 modulated by the rs2280059 genetic variant diminishes EGFR-TKIs efficiency in advanced lung adenocarcinoma. (PMID:32815538)
• Functional differences between Hsp105/110 family proteins in cell proliferation, cell division, and drug sensitivity. (PMID:34617313)
• HSP105 expression in cutaneous malignant melanoma: Correlation with clinicopathological characteristics. (PMID:34618840)
• Extracellular vesicles related gene HSPH1 exerts anti-tumor effects in prostate cancer via promoting the stress response of CD8 + T cells. (PMID:38165608)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	hsph1	ENSDARG00000019874
mus_musculus	Hsph1	ENSMUSG00000029657
rattus_norvegicus	Hsph1	ENSRNOG00000000902
drosophila_melanogaster	Hsp110	FBGN0026418
caenorhabditis_elegans	hsp-70	WBGENE00002026
caenorhabditis_elegans		WBGENE00009691
caenorhabditis_elegans		WBGENE00009692
caenorhabditis_elegans		WBGENE00016250

Paralogs (13): HSPA5 (ENSG00000044574), HSPA8 (ENSG00000109971), HSPA9 (ENSG00000113013), HSPA2 (ENSG00000126803), HYOU1 (ENSG00000149428), HSPA13 (ENSG00000155304), HSPA4L (ENSG00000164070), HSPA4 (ENSG00000170606), HSPA6 (ENSG00000173110), HSPA14 (ENSG00000187522), HSPA1B (ENSG00000204388), HSPA1A (ENSG00000204389), HSPA1L (ENSG00000204390)

Protein

Protein identifiers

Heat shock protein 105 kDa — Q92598 (reviewed: Q92598)

Alternative names: Antigen NY-CO-25, Heat shock 110 kDa protein, Heat shock protein family H member 1

All UniProt accessions (4): A0A0A0MSM0, Q92598, Q5TBM3, R4GN69

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a nucleotide-exchange factor (NEF) for chaperone proteins HSPA1A and HSPA1B, promoting the release of ADP from HSPA1A/B thereby triggering client/substrate protein release. Prevents the aggregation of denatured proteins in cells under severe stress, on which the ATP levels decrease markedly. Inhibits HSPA8/HSC70 ATPase and chaperone activities.

Subunit / interactions. Interacts with HSPA8/HSC70. Interacts with HSPA1A (via NBD) and HSPA1B (via NBD).

Subcellular location. Cytoplasm.

Tissue specificity. Highly expressed in testis. Present at lower levels in most brain regions, except cerebellum. Overexpressed in cancer cells.

Post-translational modifications. Phosphorylation on Ser-509 may be important for regulation of the HSPA8/HSC70 chaperone activity.

Similarity. Belongs to the heat shock protein 70 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q92598-1	Alpha	yes
Q92598-2	Beta
Q92598-3	3
Q92598-4	4

RefSeq proteins (5): NP_001273432, NP_001273433, NP_001273434, NP_001336633, NP_006635* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013126	Hsp_70_fam	Family
IPR018181	Heat_shock_70_CS	Conserved_site
IPR029047	HSP70_peptide-bd_sf	Homologous_superfamily
IPR029048	HSP70_C_sf	Homologous_superfamily
IPR042053	HSPH1_NBD	Domain
IPR043129	ATPase_NBD	Homologous_superfamily

Pfam: PF00012

UniProt features (58 total): strand 17, helix 17, modified residue 8, compositionally biased region 6, splice variant 3, turn 3, region of interest 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6GFA	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92598-F1	85.31	0.75

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (8): 2, 471, 509, 510, 557, 561, 809, 815

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-3000484	Scavenging by Class F Receptors
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-3371511	HSF1 activation
R-HSA-3371568	Attenuation phase
R-HSA-3371571	HSF1-dependent transactivation

MSigDB gene sets: 360 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, ELVIDGE_HYPOXIA_DN, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, PEREZ_TP63_TARGETS, AMIT_EGF_RESPONSE_60_HELA, GGAMTNNNNNTCCY_UNKNOWN, BILD_SRC_ONCOGENIC_SIGNATURE, USF_C, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, KOINUMA_COLON_CANCER_MSI_DN, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, PUJANA_CHEK2_PCC_NETWORK, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_DN

GO Biological Process (5): protein folding (GO:0006457), response to unfolded protein (GO:0006986), positive regulation of MHC class I biosynthetic process (GO:0045345), positive regulation of NK T cell activation (GO:0051135), response to stress (GO:0006950)

GO Molecular Function (6): adenyl-nucleotide exchange factor activity (GO:0000774), ATP binding (GO:0005524), alpha-tubulin binding (GO:0043014), ATP-dependent protein folding chaperone (GO:0140662), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (9): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), microtubule (GO:0005874), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), endocytic vesicle lumen (GO:0071682)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cellular response to heat stress	3
Binding and Uptake of Ligands by Scavenger Receptors	1
HSF1-dependent transactivation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cellular process	1
protein maturation	1
response to topologically incorrect protein	1
positive regulation of macromolecule biosynthetic process	1
MHC class I biosynthetic process	1
regulation of MHC class I biosynthetic process	1
positive regulation of alpha-beta T cell activation	1
NK T cell activation	1
regulation of NK T cell activation	1
response to stimulus	1
ATP binding	1
ADP binding	1
ATPase regulator activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
tubulin binding	1
protein folding chaperone	1
ATP-dependent activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
cellular_component	1
extracellular vesicle	1
endocytic vesicle	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

3737 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSPH1	SGTA	O43765	985
HSPH1	BAG2	O95816	955
HSPH1	HSPA8	P11142	955
HSPH1	DNAJB1	P25685	860
HSPH1	HSPB1	P04792	850
HSPH1	HSPB8	Q9UJY1	790
HSPH1	HSP90AA1	P07900	770
HSPH1	HSP90AB1	P08238	765
HSPH1	HSPA4	P34932	717
HSPH1	DNAJA1	P31689	704
HSPH1	HSPE1	P61604	692
HSPH1	HSPA1A	P08107	684
HSPH1	HSPB2	Q16082	677
HSPH1	DNAJB14	Q8TBM8	677
HSPH1	HSPB3	Q12988	662

IntAct

206 interactions, top by confidence:

A	B	Type	Score
YAP1	MPDZ	psi-mi:“MI:0914”(association)	0.780
DNAJB4	DNAJB5	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
CEP104	CCDC66	psi-mi:“MI:2364”(proximity)	0.540
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
DLD	PDHB	psi-mi:“MI:0914”(association)	0.530
CREB1	HSPA4L	psi-mi:“MI:0914”(association)	0.530
DNAJB4	SYNM	psi-mi:“MI:0914”(association)	0.530
TUSC2	HSPA8	psi-mi:“MI:0914”(association)	0.530
P/V	IRS4	psi-mi:“MI:0914”(association)	0.530
P/V	HSPA4L	psi-mi:“MI:0914”(association)	0.530
HSPA8	ARHGEF10	psi-mi:“MI:2364”(proximity)	0.480
EGFR	HSPH1	psi-mi:“MI:0915”(physical association)	0.470
env	PGRMC1	psi-mi:“MI:0914”(association)	0.460
HNF1A	HSPA4L	psi-mi:“MI:0914”(association)	0.420
AATK	NDUFA4	psi-mi:“MI:0914”(association)	0.420
HSPH1	Phlda1	psi-mi:“MI:0915”(physical association)	0.400
Phlda1	HSPH1	psi-mi:“MI:0915”(physical association)	0.400
HSPH1	YWHAZ	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (608): HSPH1 (Affinity Capture-MS), HSPH1 (Affinity Capture-MS), HSPH1 (Affinity Capture-MS), HSPH1 (Affinity Capture-MS), HSPH1 (Affinity Capture-MS), HSPH1 (Affinity Capture-MS), HSPH1 (Affinity Capture-MS), ASS1 (Co-fractionation), CCT2 (Co-fractionation), DNAJA1 (Co-fractionation), DNAJA2 (Co-fractionation), DNAJA4 (Co-fractionation), DNAJB1 (Co-fractionation), DNAJB4 (Co-fractionation), DNAJC3 (Co-fractionation)

ESM2 similar proteins: A2X6S3, A2YR10, A4FUX8, O88600, O94805, O95757, O96019, P30172, P32390, P34932, P42528, P47117, P48722, P53458, P53490, P78712, P81228, P81229, P86173, P93372, P93374, P93375, Q0IEG8, Q0IIM3, Q2TFN9, Q4R333, Q5R606, Q5R8R4, Q5RDM4, Q60446, Q61316, Q61699, Q61WW9, Q66HA8, Q69YN2, Q6K908, Q6ZJW9, Q84M92, Q92598, Q96482

Diamond homologs: A2Q0Z1, A5A8V7, F4HQD4, O59838, O59855, O65719, O73885, O74225, O88600, O93866, O95757, O97125, P02827, P08108, P09435, P09446, P0CB32, P0DMV8, P0DMV9, P0DMW0, P0DMW1, P10591, P10592, P11142, P16019, P17879, P18694, P19120, P19378, P22202, P22953, P24629, P26413, P27322, P27541, P29357, P32589, P32590, P34930, P34931

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
HSPH1	“up-regulates quantity by expression”	HSPA1A	“transcriptional regulation”
HSPH1	“up-regulates quantity by expression”	HSPA1B	“transcriptional regulation”
CSNK2A1	“down-regulates activity”	HSPH1	phosphorylation
CSNK2A2	“down-regulates activity”	HSPH1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 251 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Insulin receptor signalling cascade	7	26.4×	9e-07
SHC1 events in EGFR signaling	6	24.1×	1e-05
Constitutive Signaling by EGFRvIII	6	24.1×	1e-05
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	8	23.3×	4e-07
Signaling by ERBB2 ECD mutants	6	22.6×	1e-05
GRB2 events in EGFR signaling	5	21.4×	8e-05
Erythropoietin activates RAS	5	21.4×	8e-05
Tie2 Signaling	6	20.3×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein refolding	7	20.1×	4e-05
cellular response to gamma radiation	5	13.9×	4e-03
response to unfolded protein	9	12.5×	4e-05
autophagosome maturation	7	11.3×	8e-04
insulin receptor signaling pathway	9	9.2×	3e-04
mitophagy	6	8.8×	6e-03
mitotic spindle organization	7	8.8×	2e-03
positive regulation of miRNA transcription	6	8.0×	9e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

128 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	8
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2040 predictions. Top by Δscore:

Variant	Effect	Δscore
13:31137520:AATTC:A	acceptor_gain	1.0000
13:31137521:ATTC:A	acceptor_gain	1.0000
13:31137522:TTC:T	acceptor_gain	1.0000
13:31137523:TC:T	acceptor_gain	1.0000
13:31137524:CC:C	acceptor_gain	1.0000
13:31137524:CCTAA:C	acceptor_loss	1.0000
13:31137525:C:CC	acceptor_gain	1.0000
13:31137525:C:T	acceptor_gain	1.0000
13:31138403:TCA:T	donor_loss	1.0000
13:31138404:CA:C	donor_loss	1.0000
13:31138405:A:AC	donor_gain	1.0000
13:31138405:AC:A	donor_gain	1.0000
13:31138406:C:CC	donor_gain	1.0000
13:31138406:CC:C	donor_gain	1.0000
13:31138406:CCTT:C	donor_gain	1.0000
13:31138406:CCTTG:C	donor_gain	1.0000
13:31138564:TCATC:T	acceptor_gain	1.0000
13:31138565:CATC:C	acceptor_gain	1.0000
13:31138565:CATCC:C	acceptor_gain	1.0000
13:31138566:ATC:A	acceptor_gain	1.0000
13:31138567:TC:T	acceptor_gain	1.0000
13:31138567:TCCTG:T	acceptor_loss	1.0000
13:31138568:CC:C	acceptor_gain	1.0000
13:31138569:C:CC	acceptor_gain	1.0000
13:31138569:C:T	acceptor_gain	1.0000
13:31138570:T:A	acceptor_loss	1.0000
13:31138776:CTCA:C	donor_gain	1.0000
13:31138777:TCAC:T	donor_loss	1.0000
13:31138777:TCACC:T	donor_gain	1.0000
13:31138779:A:AC	donor_gain	1.0000

AlphaMissense

5724 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:31145708:A:T	V480D	1.000
13:31148476:G:T	A381E	1.000
13:31149967:C:T	G375E	1.000
13:31161530:G:T	A18D	1.000
13:31161536:G:T	A16E	1.000
13:31140251:A:T	V638D	0.999
13:31140264:C:G	A634P	0.999
13:31145663:G:T	A495E	0.999
13:31145756:A:T	V464D	0.999
13:31148452:A:T	V389D	0.999
13:31148478:A:C	C380W	0.999
13:31148480:A:G	C380R	0.999
13:31149961:G:T	A377E	0.999
13:31149963:A:C	C376W	0.999
13:31149968:C:G	G375R	0.999
13:31149968:C:T	G375R	0.999
13:31150054:C:G	R346P	0.999
13:31151021:G:C	S278R	0.999
13:31151021:G:T	S278R	0.999
13:31151023:T:G	S278R	0.999
13:31151727:C:T	G182E	0.999
13:31152854:G:T	A176D	0.999
13:31152920:C:G	R154P	0.999
13:31152922:C:A	R153S	0.999
13:31152922:C:G	R153S	0.999
13:31152923:C:G	R153T	0.999
13:31154640:A:T	V141D	0.999
13:31154676:G:T	A129D	0.999
13:31154677:C:G	A129P	0.999
13:31158816:G:T	A52D	0.999

dbSNP variants (sampled 300 via entrez): RS1000123630 (13:31160021 T>C), RS1000234118 (13:31164124 A>G), RS1000264092 (13:31140659 A>G), RS1000307313 (13:31157171 T>C,G), RS1000320240 (13:31148822 T>A,C), RS1000463119 (13:31159839 A>G,T), RS1000538903 (13:31144905 C>T), RS1000616798 (13:31139225 G>A), RS1000647933 (13:31141811 C>CACAA), RS1000707119 (13:31135509 G>C,T), RS1000904770 (13:31147313 A>G), RS1000925685 (13:31150241 G>A), RS1000996976 (13:31161270 T>C,G), RS1001050731 (13:31161407 C>A,T), RS1001079108 (13:31160878 A>C,G)

Disease associations

OMIM: gene MIM:610703 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_1999	Metabolite levels	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010542	ureidopropionic acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3706560 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items; also 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
HSPH1 T17 DELETION	Fluorouracil + Oxaliplatin	Colorectal Cancer	Sensitivity/Response	CIViC B	EID1164
HSPH1 NUCLEAR EXPRESSION	Fluorouracil + Cisplatin	Gastric Adenocarcinoma	Sensitivity/Response	CIViC D	EID1163

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 5 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.52	Kd	2991	nM	CHEMBL3752910
5.52	ED50	2991	nM	CHEMBL3752910
5.06	Kd	8649	nM	CHEMBL5653589
5.06	ED50	8649	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 33 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148560: Binding affinity to human HSPH1 incubated for 45 mins by Kinobead based pull down assay	kd	2.9906	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148560: Binding affinity to human HSPH1 incubated for 45 mins by Kinobead based pull down assay	kd	8.6487	uM

CTD chemical–gene interactions

151 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	7
methylmercuric chloride	increases expression, affects reaction, affects cotreatment	5
sodium arsenite	decreases expression, increases abundance, affects cotreatment, increases expression	5
bisphenol A	affects expression, decreases expression	3
Arsenic Trioxide	increases expression	3
Air Pollutants	increases expression, decreases expression, increases abundance	3
Arsenic	increases methylation, increases abundance, increases expression, affects cotreatment	3
Cadmium	increases palmitoylation, increases expression, decreases reaction, increases abundance	3
Copper	increases abundance, increases expression, affects binding, decreases expression, affects cotreatment	3
Valproic Acid	increases expression, affects expression	3
Cyclosporine	decreases expression, increases expression	3
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, decreases expression, increases expression	3
cobaltous chloride	increases expression	2
celastrol	increases expression, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
Acetaminophen	increases expression	2
Estradiol	affects binding, increases reaction, increases expression	2
Ivermectin	affects cotreatment, increases expression, decreases expression	2
Nickel	increases expression	2
Silicon Dioxide	affects secretion, increases expression	2
Silver	increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tetrachlorodibenzodioxin	decreases expression, affects expression	2
Dronabinol	decreases expression	2
Lactic Acid	increases expression	2
p-Chloromercuribenzoic Acid	increases expression, affects cotreatment	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
lasiocarpine	increases expression	1

ChEMBL screening assays

18 unique, capped per target: 14 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3630216	Functional	Decrease in Hsp105 expression in human U251MG cells at 5 uM for 1 hr by mass spectrometry relative to control	Hirsutinolide Series Inhibit Stat3 Activity, Alter GCN1, MAP1B, Hsp105, G6PD, Vimentin, TrxR1, and Importin α-2 Expression, and Induce Antitumor Effects against Human Glioma. — J Med Chem
CHEMBL5145382	Binding	Binding affinity to HSPH1 in human DOHH-2 cells by MS analysis	PES derivative PESA is a potent tool to globally profile cellular targets of PES. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1ND	Abcam K-562 HSPH1 KO	Cancer cell line	Female
CVCL_D2JY	Abcam Raji HSPH1 KO	Cancer cell line	Male
CVCL_UQ79	Abcam Jurkat HSPH1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.