Alternative titles; symbols
HGNC Approved Gene Symbol: HSP90AA1
Cytogenetic location: 14q32.31 Genomic coordinates (GRCh38): 14:102,080,742-102,139,749 (from NCBI)
HSP90 proteins are highly conserved molecular chaperones that have key roles in signal transduction, protein folding, protein degradation, and morphologic evolution. HSP90 proteins normally associate with other cochaperones and play important roles in folding newly synthesized proteins or stabilizing and refolding denatured proteins after stress. There are 2 major cytosolic HSP90 proteins, HSP90AA1, an inducible form, and HSP90AB1 (140572), a constitutive form. Other HSP90 proteins are found in endoplasmic reticulum (HSP90B1; 191175) and mitochondria (TRAP1; 606219) (Chen et al., 2005).
In humans, 2 distinct HSP90 cDNA clones were identified that hybrid-select different mRNA transcripts encoding 2 members of the HSP90 family. These were called HSP89-alpha and HSP89-beta (Hickey et al., 1986; Simon et al., 1987).
By database analysis, Chen et al. (2005) identified several HSP90AA1 variants encoding proteins of 413, 635, 732, and 854 amino acids. Like other HSP90 proteins, the 732-amino acid HSP90AA1 protein has a highly conserved N-terminal domain, a charged domain, a middle domain involved in ATPase activity, a second charged domain, and a C-terminal domain. It also has a 4-helical cytokine motif, a gln-rich region, and a C-terminal MEEVD motif characteristic of cytosolic HSP90 proteins. The 854-amino acid HSP90AA1 isoform has an N-terminal extension compared with the 732-amino acid isoform, but is otherwise identical.
Chimeric CD47/HSP90AA1 Transcript
By screening a T-lymphoblastic leukemia cell line (CEM) cDNA library with a probe originally isolated from a pancreatic cancer cDNA library, Schweinfest et al. (1998) cloned a variant of HSPCA that they designated HSP89-alpha-delta-N. The deduced 539-amino acid variant protein has a calculated molecular mass of about 63 kD. It has a unique 30-amino acid N terminus instead of the 223-amino acid ATP/geldanamycin-binding domain found at the N terminus of full-length HSPCA, which contains 732 amino acids. RT-PCR analysis detected expression of the variant in CEM cells and several pancreatic cell lines, as well as in normal pancreatic tissue. In vitro transcription/translation produced a protein with an apparent molecular mass of about 70 kD.
Chen et al. (2005) determined that the HSP89-alpha-delta-N transcript, which they called HSP90N, is a chimera, with the first 105 bp of the coding sequence derived from the CD47 gene (601028) on chromosome 3q13.2, and the remaining coding sequence derived from HSP90AA1.
Stepanova et al. (1996) found that CDC37 (605065) and HSP90 associate preferentially with the fraction of CDK4 (123829) not bound to D-type cyclins. Pharmacologic inactivation of CDC37/HSP90 function leads to reduced stability of CDK4.
CD14 (158120) and lipopolysaccharide (LPS)-binding protein (LBP; 151990) are major receptors for LPS; however, binding analyses and TNF production assays have suggested the presence of additional cell surface receptors, designated LPS-associated proteins (LAPs), that are distinct from CD14, LBP, and the Toll-like receptors (see TLR4; 603030). Using affinity chromatography, peptide mass fingerprinting, and fluorescence resonance energy transfer, Triantafilou et al. (2001) identified 4 diverse proteins, heat-shock cognate protein (HSPA8; 600816), HSP90A, chemokine receptor CXCR4 (162643), and growth/differentiation factor-5 (GDF5; 601146), on monocytes that form an activation cluster after LPS ligation and are involved in LPS signal transduction. Antibody inhibition analysis suggested that disruption of cluster formation abrogates TNF release. Triantafilou et al. (2001) proposed that heat shock proteins, which are highly conserved from bacteria to eukaryotic cells, are remnants of an ancient system of antigen presentation and defense against microbial pathogens.
Huntington disease (HD; 143100) is a progressive neurodegenerative disorder with no effective treatment. Geldanamycin is a benzoquinone ansamycin that binds to the heat-shock protein Hsp90 (Stebbins et al., 1997) and activates a heat-shock response in mammalian cells. Sittler et al. (2001) showed that treatment of mammalian cells with geldanamycin at nanomolar concentrations induced the expression of Hsp40 (see 604572), Hsp70 (see 140550), and Hsp90 and inhibited HD exon 1 protein aggregation in a dose-dependent manner. Similar results were obtained by overexpression of Hsp70 and Hsp40 in a separate cell culture model of HD. The authors proposed that this may provide the basis for the development of a novel pharmacotherapy for HD and related glutamine repeat disorders.
Chen et al. (2002) identified CDC37 and HSP90 as 2 additional components of the I-kappa-B kinase (IKK) complex. This complex also contains 2 catalytic subunits, IKK-alpha (600664) and IKK-beta (603258), and a regulatory subunit, NEMO (300248).
Morphologic alterations occur in Drosophila melanogaster when function of Hsp90 is compromised during development. Genetic selection maintains the altered phenotypes in subsequent generations (Rutherford and Lindquist, 1998). Queitsch et al. (2002) showed, however, that phenotypic variation still occurs in nearly isogenic recombinant inbred strains of Arabidopsis thaliana. Using a D. melanogaster strain with a dominant allele of the segmentation gene Kruppel, Sollars et al. (2003) confirmed this finding and presented evidence supporting an epigenetic mechanism for Hsp90's capacitor function, whereby reduced activity of Hsp90 induces a heritably altered chromatin state. The altered chromatin state is evidenced by ectopic expression of the morphogen 'wingless' in eye imaginal discs and a corresponding abnormal eye phenotype, both of which are epigenetically heritable in subsequent generations, even when function of Hsp90 is restored. Mutations in 9 different genes of the trithorax group that encode chromatin-remodeling proteins also induced the abnormal phenotype. These findings suggested that Hsp90 acts as a capacitor for morphologic evolution through epigenetic and genetic mechanisms. Rutherford and Henikoff (2003) commented that the evidence that heritable epigenetic variation is common raises questions about the contribution of epigenetic variation to quantitative traits in general. They stated that the nature of quantitative-trait variation is one of the last unexplored frontiers in genetics.
Young et al. (2003) showed that the cytosolic chaperones HSP90 and HSP70 dock onto a specialized tetratricopeptide (TPR) domain in the import receptor TOMM70 (606081) at the outer mitochondrial membrane. This interaction served to deliver a set of preproteins to the receptor for subsequent membrane translocation dependent on the HSP90 ATPase. Disruption of the chaperone/TOMM70 recognition inhibited the import of these preproteins into mitochondria. Young et al. (2003) proposed a mechanism in which chaperones are recruited for a specific targeting event by a membrane-bound receptor.
HSP90 is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signaling proteins, including HER2/ERBB2 (164870), AKT (164730), RAF1 (164760), BCR-ABL (151410), and mutated p53 (191170). HSP90 inhibitors bind to HSP90, and induce the proteasomal degradation of HSP90 client proteins. Although HSP90 is highly expressed in most cells, HSP90 inhibitors selectively kill cancer cells compared to normal cells, and the HSP90 inhibitor 17-allylaminogeldanamycin (17-AAG) exhibited antitumor activity in preclinical models (Solit et al., 2002). Kamal et al. (2003) reported that HSP90 derived from tumor cells has a 100-fold higher binding affinity for 17-AAG than does HSP90 from normal cells. Tumor HSP90 is present entirely in multichaperone complexes with high ATPase activity, whereas HSP90 from normal tissues is in a latent, uncomplexed state. In vitro reconstitution of chaperone complexes with HSP90 resulted in increased binding affinity to 17-AAG, and increased ATPase activity. Kamal et al. (2003) concluded that their results suggested that tumor cells contain HSP90 complexes in an activated, high-affinity conformation that facilitates malignant progression, and that may represent a unique target for cancer therapeutics.
Ficker et al. (2003) demonstrated that the cytosolic chaperones HSP70 and HSP90 interact directly with the core-glycosylated form of the wildtype HERG (152427) gene product (the alpha subunit of the I(Kr) cardiac potassium channel) present in the ER, but not the fully glycosylated, cell surface form. Trafficking-deficient mutants remained tightly associated with HSP70 and HSP90 in the ER, whereas a nonfunctional but trafficking HERG was released from the chaperones during maturation, comparable to the wildtype. Ficker et al. (2003) concluded that HSP90 and HSP70 are crucial for the maturation of wildtype HERG as well as the retention of trafficking-deficient HERG mutants.
Eustace et al. (2004) identified HSP90 as an important extracellular mediator of cancer cell invasion. HSP90A, but not HSP90B (140572), was expressed extracellularly on fibrosarcoma and breast cancer cells. HSP90A interacted with MMP2 (120360) outside the cell and promoted MMP2 activation, which is critical for tumor invasiveness.
To investigate whether the expression of telomerase subunits, of which HSP90 is one, is reflected in the malignant transition of pheochromocytomas, Boltze et al. (2003) determined mRNA and/or protein expression in 28 benign and 9 malignant pheochromocytomas and compared the results with telomerase activity. HSP90 was increased in malignant pheochromocytomas, but was also expressed at a lower level in benign tumors. TERT (187270) was clearly associated with aggressive biologic behavior. The authors concluded that TERT, HSP90, and telomerase activity are upregulated in malignant cells of the adrenal medulla.
Using recombinant human and bovine proteins for pull-down assays, Okada et al. (2004) showed that the Ca(2+)-binding protein S100A1 (176940), but not calmodulin (see CALM1, 114180), interacted with heat-shock chaperone components HSP90, HSP70, FKBP52 (FKBP4; 600611), and CYP40 (PPID; 601753). Coimmunoprecipitation studies confirmed the interactions. S100A1 contributed to protein refolding in the HSP70/HSP90 multichaperone complex.
Nitric oxide (NO) is a paracrine mediator of vascular and platelet function that is produced in the vasculature by NO synthase-3 (NOS3; 163729). Using human platelets, Ji et al. (2007) demonstrated that polymerization of beta-actin (ACTB; 102630) regulated the activation state of NOS3, and hence NO formation, by altering its binding to HSP90. NOS3 bound the globular, but not the filamentous, form of beta-actin, and the affinity of NOS3 for globular beta-actin was, in turn, increased by HSP90. Formation of this ternary complex of NOS3, globular beta-actin, and HSP90 increased NOS activity and cyclic GMP, an index of bioactive NO, and increased the rate of HSP90 degradation, thus limiting NOS3 activation. Ji et al. (2007) concluded that beta-actin regulates NO formation and signaling in platelets.
Ruden et al. (2005) reviewed the transgenerational epigenetic effects mediated by Hsp90 inhibition and diethylstilbesterol (DES). They proposed that transgenerational epigenetic phenomena involving Hsp90 and DES are related and that chromatin-mediated WNT (WNT1; 164820) signaling modifications are required for both. The authors suggested that inhibitors of Hsp90, WNT signaling, and chromatin-remodeling enzymes might function as anticancer agents by interfering with epigenetic reprogramming and canalization in cancer stem cells.
Some heat-shock proteins, such as HSP90, can be antiapoptotic and are the targets of anticancer drugs. Increased IP6K2 (606992) activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. Using mouse tissues and human cell lines, Chakraborty et al. (2008) showed that HSP90 physiologically bound IP6K2 and inhibited its catalytic activity. Drugs and selective mutations that abolished HSP90-IP6K2 binding elicited activation of IP6K2, leading to cell death. Chakraborty et al. (2008) concluded that the prosurvival actions of HSP90 reflect inhibition of IP6K2 signaling.
Cerchietti et al. (2009) showed that endogenous HSP90 interacted directly with BCL6 (109565) in diffuse large B-cell lymphomas (DLBCLs) and stabilized BCL6 mRNA and protein. HSP90 and BCL6 were almost invariantly coexpressed in the nuclei of primary DLBCL cells. HSP90 formed a complex with BCL6 at BCL6 target promoters, and pharmacologic inhibition of HSP90 derepressed BCL6 target genes.
Okiyoneda et al. (2010) identified the components of the peripheral protein quality control network that removes unfolded CFTR containing the F508del mutation (602421.0001) from the plasma membrane. Based on their results and proteostatic mechanisms at different subcellular locations, Okiyoneda et al. (2010) proposed a model in which the recognition of unfolded cytoplasmic regions of CFTR is mediated by HSC70 (600816) in concert with DNAJA1 (602837) and possibly by the HSP90 machinery. Prolonged interaction with the chaperone-cochaperone complex recruits CHIP (607207)-UBCH5C (602963) and leads to ubiquitination of conformationally damaged CFTR. This ubiquitination is probably influenced by other E3 ligases and deubiquitinating enzyme activities, culminating in accelerated endocytosis and lysosomal delivery mediated by Ub-binding clathrin adaptors and the endosomal sorting complex required for transport (ESCRT) machinery, respectively. In an accompanying perspective, Hutt and Balch (2010) commented that the 'yin-yang' balance maintained by the proteostasis network is critical for normal cellular, tissue, and organismal physiology.
Canalization, or developmental robustness, is an organism's ability to produce the same phenotype despite genotypic variations and environmental influences. Expression of a gain-of-function allele of Drosophila Kruppel results in misregulation of genes in the fly eye disc and generation of eye outgrowths, which are normally repressed via canalization. Using a fly eye outgrowth assay, Gangaraju et al. (2011) showed that a protein complex made up of Piwi (see 605571), Hsp83, and Hop (STIP1; 605063) was involved in canalization. The results suggested that canalization may involve Hsp83-mediated phosphorylation of Piwi. Gangaraju et al. (2011) concluded that the eye outgrowth phenotype is a defect in epigenetic silencing of a normally suppressed genotype.
Chen et al. (2005) determined that the HSP90AA1 gene contains 15 exons.
Ozawa et al. (1992) used 2 previously isolated distinct cDNA clones for HSP90-alpha--one from human peripheral blood lymphocytes and the other from HeLa cells transfected with the adenovirus E1A gene--to determine the organization of this gene family from 3 approaches: Southern analysis of a panel of human/hamster somatic cell hybrids, molecular cloning of cosmid clones from genomic DNA, and in situ hybridization. They demonstrated nucleotide sequences corresponding to HSP90-alpha at 4 chromosome sites: 1q21.2-q22, 4q35, 11p14.2-14.1, and 14q32.3. These were symbolized HSPCAL1, HSPCAL2, HSPCAL3, and HSPCAL4, respectively. Which of these genes are functional was not determined. Jabs (1993) indicated that the HSPCAL4 gene, which maps to chromosome 14q32, is functional.
By genomic sequence analysis, Chen et al. (2005) mapped the HSP90AA1 gene to chromosome 14q32.32. They mapped a second functional HSP90AA gene, HSP90AA2, to chromosome 11p14.1, and identified HSP90AA pseudogenes on chromosomes 1q23.1 (HSP90AA3P), 4q35.2 (HSP90AA4P), 3q27.1 (HSP90AA5P), and 4q33 (HSP90AA6P).
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