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FLASH GENE

Symbol

HSP90AA1

contributors: shn/npt/pgu - updated : 22-10-2018

HGNC name	heat shock protein 90kDa alpha (cytosolic), class A member 1
HGNC id	5253

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver       highly Endocrine pancreas         Lymphoid/Immune tonsils       highly Nervous nerve       highly Skin/Tegument skin       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow

cells

System Cell Pubmed Species Stage Rna symbol Nervous glia

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text

pancreas

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a highly conserved N-terminal domain
	two charged domains
	a middle domain involved in ATPase activity
	a 4 helical cytokine motif and a glutamin-rich region
	a C-terminal MEEVD motif

mono polymer

dimer , tetramer , hexamer , oligo

HOMOLOGY

interspecies	ortholog to hsp90a.1, Danio rerio
	ortholog to Hsp90aa1, Mus musculus
	ortholog to Hsp90aa1, Rattus norvegicus

Homologene

FAMILY

heat shock protein 90 family

CATEGORY

chaperone/stress

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,cytoplasm,cytoskeleton,microtubule
	intracellular,nucleus,nucleoplasm
text	also found in mitochondria of tumor cells
	Shuttling of the chaperones UNC45B and HSPAA1 between the A band and the Z line of the myofibril
	found in almost every compartment of eukaryotic cells
	clustered at the periciliary base

basic FUNCTION	molecular chaperone that have key roles in the protein signaling pathway, protein folding, protein degradation, and morphologic evolution
	plays a key role in the conformational maturation of oncogenic signaling proteins
	helps a variety of proteins to adopt their native conformation
	has a role in cancer cell invasion
	play important roles in folding newly synthesized proteins or stabilizing and refolding denatured proteins after stress
	having ATPase activity
	mediating the targeting of a subset of mitochondrial preproteins to the TOM70 receptor
	playing important roles in maintaining and facilitating the degenerative phenotype in degenerative diseases and provide a common principle governing cancer and neurodegenerative diseases
	playing an active role in the targeting and outer membrane translocation steps of TOMM70A-mediated mitochondrial import
	a crucial role of Hsp90 for growth and/or survival of tumor cells
	plays a key role in the conformational maturation of various transcription factors and protein kinases in signal transduction
	role in protein sorting, pointing to a central role for this molecular chaperone in the cell
	a critical role in TGFbeta signaling
	HSP90AA1, HSP90AB1 differentially modulate NO and O(2)(-) generation by eNOS (endothelial nitric oxide synthase) through promoting changes in endothelial nitric oxide synthase conformation and phosphorylation state 3)
	HSP90AA1 promotes folding of REV1 into a stable and/or functional form(s) to bind to monoubiquitinated PCNA
	BRCA1 and HSP90AA1 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation
	HSP90AA1 and HSP90B1 play key roles in controlling KCNQ4 homeostasis via the HSP40-HSP70-HOP-HSP90 chaperone pathway and the ubiquitin-proteasome pathway
	HSP90AA1 was co-localized with AHR after the nuclear translocation
	forms a stable complex at the cilium neck for the interaction of signalling molecules in IGF1 receptor signalling
	stress inducible isoform of the molecular chaperone HSP90
	HSP90AA1 and HSPA5 interact with PRDM14 and participate in cancer regulation

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

text	an essential component of the protective heat shock response

PATHWAY

metabolism

signaling

a component	can form tetra-, hexa- or dodecamers that exhibit a chaperone activity
	chaperone complex comprising HSP90AA1 and TTC1 that is recruited to the membrane protein VAPA, and regulates intracellular vesicle transport

INTERACTION

DNA

RNA

small molecule

protein	dsDNA-activated protein kinase
	pp60c-src and 50-kDa phosphoprotein
	myogenic differentiation 1, MYOD1
	androgen receptor, AR
	casein kinase II, CKII
	calmodulin
	51 kDa FKBP, FKBP51
	Ah receptor-interacting protein AIP
	52 kDa FK506-binding protein, FKBP52
	homeodomain-only protein, HOP
	FKBP51/54
	cell division cycle 37 homolog (S. cerevisiae), CDC37
	proto-oncogene MTG8 (ETO/CDR)
	phosphoprotein phosphatase 5, PP5
	tetratricopeptide repeat protein 1, TPR1
	glucocorticosteroid receptor, GR
	death-associated protein 3, DAP3
	glutamyl-prolyl-tRNA synthetase, EPRS
	Serine/threonine kinase Akt/PKB
	HBV X-associated protein 2, XAP2
	carboxyl terminus of Hsc70-interacting protein, CHIP )
	protooncogene Pim-1
	apolipoprotein B48, apoB48
	protein kinase RNA-activated, PKR
	G alpha(12)
	extracellular signal-regulated kinase 1, ERK1 and extracellular signal-regulated kinase 1, ERK2
	phosphatidylinositide-3-OH kinase (PI3K) and 3-phosphoinositide-dependent protein kinase-1, PDK1
	FKBP59, small acidic protein p23, Hsp-interacting and Hsp40
	IKKalpha, IKKbeta and NEMO
	estrogen receptor, ER
	endothelial nitric oxide synthase, eNOS
	Cyclophilin 40 (CyP40)
	asialoglycoprotein, ASGPR
	TP53
	IRE1alpha and PERK
	EGFRvIII
	peroxisome proliferator-activated receptor alpha, PPARalpha
	serine/threonine-protein kinase LKB1
	activator of Hsp90 ATPase, Aha1
	Tom70
	signal transducer and activator of transcription 3, STAT3
	telomerase reverse transcriptase, TERT
	activator of Hsp90 ATPase, Aha1 and high copy Hsp90 suppressor, Hch1
	C. jejuni surface lipoprotein JlpA
	Heat shock factor 1, HSF1
	Connexin 43, Cx43
	matrix metalloproteinase 2, MMP2
	ubiquitin fusion degradation protein 2, UFD2a and CHIP
	CDK11p46
	protein phosphatase 5, Ppp5
	v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian), ERBB2
	VEGF receptor 2 VEGFR2
	interleukin-1 receptor-associated kinase 1, IRAK1
	WAF-1/CIP1 stabilizing protein 39, WISp39 and cyclin-dependent kinase inhibitor 1A (p21, Cip1), p21
	Neural Wiskott-Aldrich syndrome protein, N-WASP
	Hsp90-associating relative of Cdc37, HARC
	small serine/threonine kinase, SSTK
	Shepherdin
	histone deacetylase 6, HDAC6
	Sp1 transcription factor, SP1
	ribosomal protein S3, rpS3
	Checkpoint kinase 1, Chk1
	hypoxia-responsive pro-apoptotic protein, HGTD-P
	Ron(M1254T)
	GC-receptor, GCR
	Breast cancer metastasis suppressor 1, BRMS1
	receptor-interacting protein 1, RIP1 and triad domain-containing protein 3, Triad3A
	orphan nuclear receptor small heterodimer partner, SHP
	N-myc downstream regulated 1, NDRG1
	Death-associated protein kinase, DAPK
	vascular endothelial growth factor receptor 3, VEGFR3
	TTC4 is a nucleoplasmic protein which interacts with HSP90AA1 and HSPA4, and also with the replication protein CDC6
	RAF1, HSF1, CDC37, and MAP2K1 interacted with both HSP90AA1 and HSP90AB1, and the relative patterns of these interactions were not affected by heat shock 4)
	TPR (tetratricopeptide repeat)-containing protein associated with Hsp (heat-shock protein) 90], Tah1
	TbetaRI and TbetaRII
	USP50 may act through a HSP90AA1-dependent mechanism to counteract CDC25B mitotic inducing activity and prevent WEE1 degradation
	TELO2-TTI1-TTI2 complex is a PIKK-specific cochaperone for HSP90AA1
	LATS1 and LATS2 are novel HSP90AA1 clients and HSP90AA1 inhibitors can disrupt the LATS tumor suppressor pathway in cancer cells
	HSP90AA1 interacts predominantly with the cytosolic, inactive pool of PI4KB, shielding it from proteolytic degradation but also sequestering it to the cytosol until an extracellular stimulus triggers its translocation to the Golgi or plasma membrane and subsequent activation
	interacts and protects GABARAPL1 from its degradation by the proteasome
	HSP90AA1 plays a critical role in the regulation of HCV RNA polymerase phosphorylation via the PDK1-PKN2 signaling pathway
	HECTD1 is a substrates of HSP90AA1
	involved in the regulation of OGT and O-GlcNAc modification and HSP90AA1 inhibitors might be used to modulate O-GlcNAc modification
	SUGT1, a cochaperone for HSP90AA1, 1s a novel PLK1 substrate during mitosis
	FKBP6 is a cochaperone that interacts with HSP90AA1
	TCF12 expression is required for secreted HSP90AA1 to enhance colorectal cancer cell spreading
	HSP90AA1 interacts and stabilizes KDM4B protein
	similar to other atypical Rho GTPases, RHOBTB2 was found to have retained the capacity to bind GTP, modulated by the HSP90AA1 ATPase cycle
	HSP90AA1 and HSP90AB1, and not HSP90B1-GRP94 or TRAP1, are responsible for maintaining proper cellular levels of ARNTL protein (r
	importance of CUL5 in multiple aspects of the cellular response to HSP90AA1 inhibition
	supports tumor growth and angiogenesis through PRKD2 protein stabilization
	in response to cellular proliferation and DNA damage, proteasome and HSP90AA1-mediated regulation of POLB and XRCC1 alters the DNA repair complex architecture
	interactions of AICDA with EEF1A1 and heat-shock protein 90 kD (HSP90AA1) are inversely correlated
	HSP90AA1 and CDC37 cochaperone complex-mediated protein folding is thus an important part of the RIPK3 activation process during necroptosis.
	FLCN is an HSP90AA1 client protein and its binding partners FNIP1/FNIP2 function as co-chaperones
	FKBP8 binding to HSP90AA1 did not substantially influence its ATPase activity
	SUGT1-HSP90AA1 complex contributes to the E3 ligase activity of the CUL4A complex that is necessary for CENPA ubiquitylation and CENPA deposition at the centromere
	UNC45B is a unique chaperone in which the TPR domain recruits HSP90AA1
	because methylation represses ESR1 activity, the observed complex formation between SMYD2 and HSP90AA1/PTGES3 may contribute to ESR1 regulation
	STIP1 is a co-chaperone of HSPA4 and HSP90AA1 that regulates a number of cell biology processes via interactions with cellular proteins
	HSP90AA1 interacted with HMGCR, the rate&
	8209;limiting enzyme of mevalonate pathway, and regulated its protein expression level by inhibiting protein degradation

cell & other

REGULATION

activated by	stress-regulated cochaperone aha1
	activator of 90 kDa heat shock protein ATPase homolog 1, AHA1
	cpr6

inhibited by	geldanamycin and radicicol
	Cdc37 can inhibit the ATPase activity of Hsp90
	HOP homeobox, HOP
	inhibition of its ATPase by its cochaperone PTGES3

Other

methylated by SMYD2 in various cell types (HSP90AA1 methylation in muscle, contributing to the formation of a protein complex containing SMYD22, HSP90AA1, and the sarcomeric protein titin)

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in gastric cancer tumoral   translocation     with BCL6 in primary diffuse large B-cell lymphomas of the central nervous system constitutional       loss of function loss of HSP90AA1 function abolishes BRCA1-dependent DSB repair tumoral     --over   highly expressed in leukemia cells

Susceptibility

Variant & Polymorphism

Candidate gene
Marker	FNIP1/FNIP2 expression can potentially serve as a predictive indicator of tumour response to HSPAA1 inhibitors
Therapy target	Hsp90 protein is an attractive pharmaceutical anti-cancer target
	System Type Disorder Pubmed cancer     modification of proteins is involved in many important cellular processes diabete     HSP90AA1 inhibitors might be used to modulate O-GlcNAc modification and reverse its adverse effects in diabetes and its complications and cardiovascular and neurodegenerative diseases

ANIMAL & CELL MODELS