Search results for HDAC6

Showing 18 results out of 30

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Protein (5 results from a total of 5)

Identifier: R-HSA-9660002
Species: Homo sapiens
Compartment: lysosomal lumen
Primary external reference: UniProt: HDAC6: Q9UBN7
Identifier: R-HSA-351589
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: HDAC6: Q9UBN7
Identifier: R-HSA-9646404
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: Q9UBN7
Identifier: R-HSA-5324660
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: Q9UBN7
Identifier: R-HSA-9659980
Species: Homo sapiens
Compartment: late endosome lumen
Primary external reference: UniProt: Q9UBN7

Reaction (5 results from a total of 17)

Identifier: R-HSA-5618331
Species: Homo sapiens
Compartment: cytosol
HDAC6 is a microtubule-associated deacetylase that targets the K40 acetyl groups of alpha tubulin (Hubbert et al, 2002; Loktev et al, 2008; Zhang et al, 2008). HDAC6 also interacts with BBIP1, a component of the BBSome that is required for BBSome assembly, and additionally (and independently of its role in the BBSome) plays a role in microtubule polymerization and acetylation (Loktev et al, 2008). Depletion of BBIP1 causes a marked reduction in cytoplasmic microtubule acetylation, and this defect is partially overcome by inhibition of HDAC6. These data suggest that BBIP1 may exert its effect on microtubule acetylation by negatively regulating HDAC6, although other mechanisms are also possible (Loktev et al, 2008).
Identifier: R-HSA-9008389
Species: Homo sapiens
Compartment: nucleoplasm
Based on studies in rat osteoblast, RUNX2 forms a complex with the histone deacetylase HDAC6 (Westendorf et al. 2002).
Identifier: R-HSA-5324632
Species: Homo sapiens
Compartment: cytosol
Proteotoxic stress results in an accumulation of misfolded proteins which tend to form insoluble protein aggregates. Histone deacetylase 6 (HDAC6) binds to ubiquitinated protein aggregates to regulate their degradation (Boyault C et al. 2006). HDAC6 was also found to interact with HSP90 and to regulate HSP90 chaperone complex activity via deacetylation of HSP90 (Kovacs JJ et al. 2005; Boyault C et al. 2007). Binding of HDAC6 to polyubiquitinted proteins triggers the dissociation of the HDAC6:HSP90:HSF1 complex resulting in the activation of HSF1 (Boyault C et al. 2007).

In the absence of stress HSF1 is predominantly monomeric and is thought to be repressed in its inactive monomeric state by the following mechanisms:

  • interaction with chaperone proteins such as HSP90 (Zou J et al.1998; Guo Y et al. 2001)
  • intramolecular coiled-coil interactions between a hydrophobic leucine zipper domain in the carboxyl-terminus of the protein and three amino-terminal leucine zippers, which are required for homotrimerization and transcriptional activation (Rabindran SK et al. 1993; Zuo J et al. 1995)
  • post-translation modifications that include protein acetylation, sumoylation and phosphorylation may also contribute to HSF1 repression (Knauf U et al. 1996; Hietakangas V et al. 2003; Batista-Nascimento L et al. 2011)
Identifier: R-HSA-9646390
Species: Homo sapiens
Compartment: cytosol
Histone deacetylase 6 (HDAC6) binds misfolded proteins destined to form aggresomes and subsequently delivers this to dynein motor proteins. HDAC6 can also bind to microtubules thereby anchoring the misfolded proteins and the dynein motor to the microtubule (Hubbert C et al. 2002). Following this, the dynein motors traverse the microtubule to reach the microtubule-organizing center (MTOC).
Identifier: R-HSA-9646354
Species: Homo sapiens
Compartment: cytosol
Histone deacetylase 6 (HDAC6) appears to be a master regulator of the cell protective response to cytotoxic protein aggregate formation (Boyault et al. 2007).

Complex (4 results from a total of 4)

Identifier: R-HSA-9008392
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-5324663
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5324677
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9008444
Species: Homo sapiens
Compartment: nucleoplasm

Set (1 results from a total of 1)

Identifier: R-HSA-9008443
Species: Homo sapiens
Compartment: nucleoplasm

Pathway (2 results from a total of 2)

Identifier: R-HSA-6807070
Species: Homo sapiens
PTEN is regulated at the level of gene transcription, mRNA translation, localization and protein stability.

Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016).

MicroRNAs miR-26A1, miR-26A2, miR-22, miR-25, miR-302, miR-214, miR-17-5p, miR-19 and miR-205 bind PTEN mRNA and inhibit its translation into protein. These microRNAs are altered in cancer and can account for changes in PTEN levels (Meng et al. 2007, Xiao et al. 2008, Yang et al. 2008, Huse et al. 2009, Kim et al. 2010, Poliseno, Salmena, Riccardi et al. 2010, Cai et al. 2013). In addition, coding and non-coding RNAs can prevent microRNAs from binding to PTEN mRNA. These RNAs are termed competing endogenous RNAs or ceRNAs. Transcripts of the pseudogene PTENP1 and mRNAs transcribed from SERINC1, VAPA and CNOT6L genes exhibit this activity (Poliseno, Salmena, Zhang et al. 2010, Tay et al. 2011, Tay et al. 2014).

PTEN can translocate from the cytosol to the nucleus after undergoing monoubiquitination. PTEN's ability to localize to the nucleus contributes to its tumor suppressive role (Trotman et al. 2007). The ubiquitin protease USP7 (HAUSP) targets monoubiquitinated PTEN in the nucleus, resulting in PTEN deubiquitination and nuclear exclusion. PML, via an unknown mechanism that involves USP7- and PML-interacting protein DAXX, inhibits USP7-mediated deubiquitination of PTEN, thus promoting PTEN nuclear localization. Disruption of PML function in acute promyelocytic leukemia, through a chromosomal translocation that results in expression of a fusion protein PML-RARA, leads to aberrant PTEN localization (Song et al. 2008).

Several ubiquitin ligases, including NEDD4, WWP2, STUB1 (CHIP), RNF146, XIAP and MKRN1, polyubiquitinate PTEN and target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Ahmed et al. 2011, Maddika et al. 2011, Lee et al. 2015, Li et al. 2015). The ubiquitin proteases USP13 and OTUD3, frequently down-regulated in breast cancer, remove polyubiquitin chains from PTEN, thus preventing its degradation and increasing its half-life (Zhang et al. 2013, Yuan et al. 2015). The catalytic activity of PTEN is negatively regulated by PREX2 binding (Fine et al. 2009, Hodakoski et al. 2014) and TRIM27-mediated ubiquitination (Lee et al. 2013), most likely through altered PTEN conformation.

In addition to ubiquitination, PTEN also undergoes SUMOylation (Gonzalez-Santamaria et al. 2012, Da Silva Ferrada et al. 2013, Lang et al. 2015, Leslie et al. 2016). SUMOylation of the C2 domain of PTEN may regulate PTEN association with the plasma membrane (Shenoy et al. 2012) as well as nuclear localization of PTEN (Bassi et al. 2013, Collaud et al. 2016). PIASx-alpha, a splicing isorom of E3 SUMO-protein ligase PIAS2 has been implicated in PTEN SUMOylation (Wang et al. 2014). SUMOylation of PTEN may be regulated by activated AKT (Lin et al. 2016). Reactions describing PTEN SUMOylation will be annotated when mechanistic details become available.

Phosphorylation affects the stability and activity of PTEN. FRK tyrosine kinase (RAK) phosphorylates PTEN on tyrosine residue Y336, which increases PTEN half-life by inhibiting NEDD4-mediated polyubiquitination and subsequent degradation of PTEN. FRK-mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).

PTEN localization and activity are affected by acetylation of its lysine residues (Okumura et al. 2006, Ikenoue et al. 2008, Meng et al. 2016). PTEN can undergo oxidation, which affects its function, but the mechanism is poorly understood (Tan et al. 2015, Shen et al. 2015, Verrastro et al. 2016).

Identifier: R-HSA-3214815
Species: Homo sapiens
Lysine deacetylases (KDACs), historically referred to as histone deacetylases (HDACs), are divided into the Rpd3/Hda1 metal-dependent 'classical HDAC family' (de Ruijter et al. 2003, Verdin et al. 2003) and the unrelated sirtuins (Milne & Denu 2008). Phylogenetic analysis divides human KDACs into four classes (Gregoretti et al. 2004): Class I includes HDAC1, 2, 3 and 8; Class IIa includes HDAC4, 5, 7 and 9; Class IIb includes HDAC6 and 10; Class III are the sirtuins (SIRT1-7); Class IV has one member, HDAC11 (Gao et al. 2002). Class III enzymes use an NAD+ cofactor to perform deacetylation (Milne & Denu 2008, Yang & Seto 2008), the others classes use a metal-dependent mechanism (Gregoretti et al. 2004) to catalyze the hydrolysis of acetyl-L-lysine side chains in histone and non-histone proteins yielding L-lysine and acetate. X-ray crystal structures are available for four human HDACs; these structures have conserved active site residues, suggesting a common catalytic mechanism (Lombardi et al. 2011). They require a single transition metal ion and are typically studied in vitro as Zn2+-containing enzymes, though in vivo HDAC8 exhibits increased activity when substituted with Fe2+ (Gantt et al. 2006). The structurally-related enzyme acetylpolyamine amidohydrolase (APAH) (Leipe & Landsman 1997) exhibits optimal activity with Mn2+, followed closely by Zn2+ (Sakurada et al. 1996).

HDACs are often part of multi-protein transcriptional complexes that are recruited to gene promoters, regulating transcription without direct DNA binding. With the exception of HDAC8, all class I members can be catalytic subunits of multiprotein complexes (Yang & Seto 2008). HDAC1 and HDAC2 interact to form the catalytic core of several multisubunit complexes including Sin3, nucleosome remodeling deacetylase (NuRD) and corepressor of REST (CoREST) complexes (Grozinger & Schreiber 2002). HDAC3 is part of the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) complex or the homologous nuclear receptor corepressor (NCoR) (Li et al. 2000, Wen et al. 2000, Zhang et al. 2002, Yoon et al. 2003, Oberoi et al. 2011) which are involved in a wide range of processes including metabolism, inflammation, and circadian rhythms (Mottis et al. 2013).

Class IIa HDACs (HDAC4, -5, -7, and -9) shuttle between the nucleus and cytoplasm (Yang & Seto 2008, Haberland et al. 2009). The nuclear export of class IIa HDACs requires phosphorylation stimulated by calcium or other stimuli. They appear to have been evolutionarily inactivated as enzymes, having acquired a histidine substitution of the tyrosine residue in the active site of the mammalian deacetylase domain (H976 in humans) (Lahm et al. 2007, Schuetz et al. 2008). Instead they function as transcriptional corepressors for the MEF2 family of transcription factors (Yang & Gregoire 2005) .

Histones are the primary substrate for most HDACs except HDAC6 which is predominantly cytoplasmic and acts on alpha-tublin (Hubbert et al. 2002, Zhang et al. 2003, Boyault et al. 2007). HDACs also deacetylate proteins such as p53, E2F1, RelA, YY1, TFIIE, BCL6 and TFIIF (Glozak et al. 2005).

Histone deacetylases are targeted by structurally diverse compounds known as HDAC inhibitors (HDIs) (Marks et al. 2000). These can induce cytodifferentiation, cell cycle arrest and apoptosis of transformed cells (Marks et al. 2000, Bolden et al. 2006). Some HDIs have significant antitumor activity (Marks and Breslow 2007, Ma et al. 2009) and at least two are approved anti-cancer drugs.

The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.

Icon (1 results from a total of 1)

Species: Homo sapiens
Histone deacetylase 6
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