DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	REST (QuickGO)	Interactive visualization of REST structures (A quick tutorial to explore the interctive visulaization) Representative structure: 2CZY
Synonyms	REST, NRSF, XBR,
Protein Name	REST
Alternative Name(s)	RE1-silencing transcription factor;Neural-restrictive silencer factor;X2 box repressor;
Protein Family	noSimilarity_annotations
EntrezGene ID	5978 (Comparitive Toxicogenomics)
UniProt AC (Human)	Q13127 (protein sequence)
Enzyme Class	N/A
Molecular Weight	121872 Dalton
Protein Length	1097 amino acids (AA)
Genome Browsers	NCBI \|
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree

Domain organization, Expression, Diseases

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Localization, Function, Catalytic activity and Sequence

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Localization (UniProt annotation)
Nucleus Cytoplasm Note=Colocalizes withZFP90 in the nucleus (By similarity) In response to hypoxia,there is a more pronounced increase in levels in the nucleus ascompared to the cytoplasm
Function (UniProt annotation)
Transcriptional repressor which binds neuron-restrictivesilencer element (NRSE) and represses neuronal gene transcriptionin non-neuronal cells Restricts the expression of neuronal genesby associating with two distinct corepressors, mSin3 and CoREST,which in turn recruit histone deacetylase to the promoters ofREST-regulated genes Mediates repression by recruiting the BHCcomplex at RE1/NRSE sites which acts by deacetylating anddemethylating specific sites on histones, thereby acting as achromatin modifier Transcriptional repression by REST-CDYL viathe recruitment of histone methyltransferase EHMT2 may beimportant in transformation suppression Key repressor of geneexpression in hypoxia; represses genes in hypoxia by directbinding to an RE1/NRSE site on their promoter regions(PubMed:27531581) Negatively regulates the expression of SRRM3 inbreast cancer cell lines (PubMed:26053433) Represses theexpression of SRRM4 in non-neural cells to prevent the activationof neural specific splicing events (By similarity) Acts as aregulator of osteoblast differentiation (By similarity)
Catalytic Activity (UniProt annotation)
N/A
Protein Sequence
MATQVMGQSSGGGGLFTSSGNIGMALPNDMYDLHDLSKAELAAPQLIMLANVALTGEVNGSCCDYLVGEERQMAELMPVG DNNFSDSEEGEGLEESADIKGEPHGLENMELRSLELSVVEPQPVFEASGAPDIYSSNKDLPPETPGAEDKGKSSKTKPFR CKPCQYEAESEEQFVHHIRVHSAKKFFVEESAEKQAKARESGSSTAEEGDFSKGPIRCDRCGYNTNRYDHYTAHLKHHTR AGDNERVYKCIICTYTTVSEYHWRKHLRNHFPRKVYTCGKCNYFSDRKNNYVQHVRTHTGERPYKCELCPYSSSQKTHLT RHMRTHSGEKPFKCDQCSYVASNQHEVTRHARQVHNGPKPLNCPHCDYKTADRSNFKKHVELHVNPRQFNCPVCDYAASK KCNLQYHFKSKHPTCPNKTMDVSKVKLKKTKKREADLPDNITNEKTEIEQTKIKGDVAGKKNEKSVKAEKRDVSKEKKPS NNVSVIQVTTRTRKSVTEVKEMDVHTGSNSEKFSKTKKSKRKLEVDSHSLHGPVNDEESSTKKKKKVESKSKNNSQEVPK GDSKVEENKKQNTCMKKSTKKKTLKNKSSKKSSKPPQKEPVEKGSAQMDPPQMGPAPTEAVQKGPVQVEPPPPMEHAQME GAQIRPAPDEPVQMEVVQEGPAQKELLPPVEPAQMVGAQIVLAHMELPPPMETAQTEVAQMGPAPMEPAQMEVAQVESAP MQVVQKEPVQMELSPPMEVVQKEPVQIELSPPMEVVQKEPVKIELSPPIEVVQKEPVQMELSPPMGVVQKEPAQREPPPP REPPLHMEPISKKPPLRKDKKEKSNMQSERARKEQVLIEVGLVPVKDSWLLKESVSTEDLSPPSPPLPKENLREEASGDQ KLLNTGEGNKEAPLQKVGAEEADESLPGLAANINESTHISSSGQNLNTPEGETLNGKHQTDSIVCEMKMDTDQNTRENLT GINSTVEEPVSPMLPPSAVEEREAVSKTALASPPATMAANESQEIDEDEGIHSHEGSDLSDNMSEGSDDSGLHGARPVPQ ESSRKNAKEALAVKAAKGDFVCIFCDRSFRKGKDYSKHLNRHLVNVYYLEEAAQGQE

Motif information from Eukaryotic Linear Motif atlas (ELM)

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Gene Ontology (P: Process; F: Function and C: Component terms)

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GO:0000122	P:negative regulation of transcription by RNA polymerase II
GO:0000381	P:regulation of alternative mRNA splicing
GO:0000978	via spliceosome
GO:0000981	F:RNA polymerase II proximal promoter sequence-specific DNA binding
GO:0001078	F:RNA polymerase II transcription factor activity
GO:0001228	sequence-specific DNA binding
GO:0001666	F:transcriptional repressor activity
GO:0002244	RNA polymerase II proximal promoter sequence-specific DNA binding
GO:0003682	F:transcriptional activator activity
GO:0003700	RNA polymerase II transcription regulatory region sequence-specific DNA binding
GO:0004407	P:response to hypoxia
GO:0005634	P:hematopoietic progenitor cell differentiation
GO:0005654	F:chromatin binding
GO:0005737	F:DNA-binding transcription factor activity
GO:0005829	F:histone deacetylase activity
GO:0006355	C:nucleus
GO:0008134	C:nucleoplasm
GO:0008285	C:cytoplasm
GO:0010629	C:cytosol
GO:0015271	P:regulation of transcription
GO:0017053	DNA-templated
GO:0032348	F:transcription factor binding
GO:0035690	P:negative regulation of cell proliferation
GO:0043065	P:negative regulation of gene expression
GO:0043280	F:outward rectifier potassium channel activity
GO:0043922	C:transcriptional repressor complex
GO:0044212	P:negative regulation of aldosterone biosynthetic process
GO:0045665	P:cellular response to drug
GO:0045666	P:positive regulation of apoptotic process
GO:0045667	P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0045892	P:negative regulation by host of viral transcription
GO:0045893	F:transcription regulatory region DNA binding
GO:0045955	P:negative regulation of neuron differentiation
GO:0046676	P:positive regulation of neuron differentiation
GO:0046872	P:regulation of osteoblast differentiation
GO:0050768	P:negative regulation of transcription
GO:0060379	DNA-templated
GO:0070933	P:positive regulation of transcription
GO:0071257	DNA-templated
GO:0071385	P:negative regulation of calcium ion-dependent exocytosis
GO:2000065	P:negative regulation of insulin secretion
GO:2000706	F:metal ion binding
GO:2000740	P:negative regulation of neurogenesis
GO:2000798	P:cardiac muscle cell myoblast differentiation
	P:histone H4 deacetylation

KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
hsa04550	Signaling pathways regulating pluripotency of stem cells	Pluripotent stem cells (PSCs) are basic cells with an indefinite self-renewal capacity and the potential to generate all the cell types of the three germinal layers. The types of PSCs known to date include embryonic stem (ES) and induced pluripotent stem (iPS) cells. ES cells are derived from the inner cell mass (ICM) of blastocyst-stage embryos. iPS cells are generated by reprogramming somatic cells back to pluripotent state with defined reprogramming factors, Oct4, Sox2, Klf4 and c-Myc (also known as Yamanaka factors). PSCs including ES cells and iPS cells are categorized into two groups by their morphology, gene expression profile and external signal dependence. Conventional mouse-type ES/iPS cells are called 'naive state' cells. They are mainly maintained under the control of LIF and BMP signaling. On the other hand, human-type ES/iPS cells, which are in need of Activin and FGF signaling, are termed 'primed state'. However, these signaling pathways converge towards the activation of a core transcriptional network that is similar in both groups and involves OCt4, Nanog and Sox2. The three transcription factors and their downstream target genes coordinately promote self-renewal and pluripotency.
hsa05016	Huntington disease	Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). The symptoms are choreiform, involuntary movements, personality changes and dementia. HD is caused by a CAG repeat expansion in the IT15gene, which results in a long stretch of polyglutamine close to the amino-terminus of the HD protein huntingtin (Htt). Mutant Htt (mHtt) has effects both in the cytoplasm and in the nucleus. In the cytoplasm, full-length mHtt can interfere with BDNF vesicular transport on microtubules. This mutant protein also may lead to abnormal endocytosis and secretion in neurons, because normal Htt form a complex with the proteins Hip1, clathrin and AP2 that are involved in endocytosis. In addition, mHtt affects Ca2+ signaling by sensitizing InsP3R1 to activation by InsP3, stimulating NMDAR activity, and destabilizing mitochondrial Ca2+ handling. The mHtt translocates to the nucleus, where it forms intranuclear inclusions. Nuclear toxicity is believed to be caused by interference with gene transcription, leading to loss of transcription of neuroprotective molecules such as BDNF. While mHtt binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity. Augmented p53 mediates mitochondrial dysfunction.

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-3214815	HDACs deacetylate histones.	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
R-HSA-8943724	Regulation of PTEN gene transcription.	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)

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REST