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Protein

mRNA decay activator protein ZFP36

Gene

Zfp36

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Zinc-finger RNA-binding protein that destabilizes numerous cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthesis (PubMed:27193233). Acts as an 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery. Recruits deadenylase CNOT7 (and probably the CCR4-NOT complex) via association with CNOT1, and hence promotes ARE-mediated mRNA deadenylation. Functions also by recruiting components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs. Self regulates by destabilizing its own mRNA (By similarity). Binds to 3'-UTR ARE of numerous mRNAs (PubMed:27193233). Binds also to ARE of its own mRNA. Plays a role in anti-inflammatory responses; suppresses tumor necrosis factor (TNF)-alpha production by stimulating ARE-mediated TNF-alpha mRNA decay and several other inflammatory ARE-containing mRNAs in interferon (IFN)- and/or lipopolysaccharide (LPS)-induced macrophages. Plays also a role in the regulation of dendritic cell maturation at the post-transcriptional level, and hence operates as part of a negative feedback loop to limit the inflammatory response. Promotes ARE-mediated mRNA decay of hypoxia-inducible factor HIF1A mRNA during the response of endothelial cells to hypoxia. Positively regulates early adipogenesis of preadipocytes by promoting ARE-mediated mRNA decay of immediate early genes (IEGs). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA. Plays a role in maintaining skeletal muscle satellite cell quiescence by promoting ARE-mediated mRNA decay of the myogenic determination factor MYOD1 mRNA. Associates also with and regulates the expression of non-ARE-containing target mRNAs at the post-transcriptional level, such as MHC class I mRNAs. Participates in association with argonaute RISC catalytic components in the ARE-mediated mRNA decay mechanism; assists microRNA (miRNA) targeting ARE-containing mRNAs. May also play a role in the regulation of cytoplasmic mRNA decapping; enhances decapping of ARE-containing RNAs, in vitro. Involved in the delivery of target ARE-mRNAs to processing bodies (PBs). In addition to its cytosolic mRNA-decay function, affects nuclear pre-mRNA processing. Negatively regulates nuclear poly(A)-binding protein PABPN1-stimulated polyadenylation activity on ARE-containing pre-mRNA during LPS-stimulated macrophages. Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion. Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis. Plays a role as a tumor suppressor by inhibiting cell proliferation in breast cancer cells (By similarity).By similarity1 Publication

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri96 – 124C3H1-type 1PROSITE-ProRule annotationAdd BLAST29
Zinc fingeri134 – 162C3H1-type 2PROSITE-ProRule annotationAdd BLAST29

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Ribonucleoprotein

Keywords - Biological processi

mRNA transport, Transport

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Names & Taxonomyi

Protein namesi
Recommended name:
mRNA decay activator protein ZFP36Curated
Alternative name(s):
TPA-induced sequence 11By similarity
TristetraprolinBy similarity
Zinc finger protein 36Imported
Short name:
Zfp-36By similarity
Gene namesi
Name:Zfp36Imported
Synonyms:Tis111 Publication, TtpBy similarity
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi620722. Zfp36.

Subcellular locationi

  • Nucleus 1 Publication
  • Cytoplasm 1 Publication
  • Cytoplasmic granule By similarity
  • CytoplasmP-body By similarity

  • Note: Shuttles between nucleus and cytoplasm in a CRM1-dependent manner (PubMed:12054509). Localized predominantly in the cytoplasm in a p38 MAPK- and YWHAB-dependent manner. Colocalizes with SH3KBP1 and MAP3K4 in the cytoplasm. Component of cytoplasmic stress granules (SGs). Localizes to cytoplasmic stress granules upon energy starvation. Localizes in processing bodies (PBs). Excluded from stress granules in a phosphorylation MAPKAPK2-dependent manner. Shuttles in and out of both cytoplasmic P-body and SGs (By similarity).By similarity1 Publication

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Exosome, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi3L → A: Inhibits nucleus export. 1 Publication1
Mutagenesisi10L → A: Inhibits nucleus export. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000891651 – 320mRNA decay activator protein ZFP36Add BLAST320

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei53Phosphoserine; by MAPKAPK2By similarity1
Modified residuei59PhosphoserineBy similarity1
Modified residuei81PhosphoserineBy similarity1
Modified residuei83PhosphoserineBy similarity1
Modified residuei85PhosphothreonineBy similarity1
Modified residuei86PhosphoserineBy similarity1
Modified residuei179Phosphoserine; by MAPKAPK2By similarity1
Modified residuei190PhosphoserineBy similarity1
Modified residuei211PhosphoserineBy similarity1
Modified residuei221Phosphoserine; by MAPK1; in vitroBy similarity1
Modified residuei251PhosphothreonineBy similarity1
Modified residuei270PhosphoserineBy similarity1
Modified residuei290PhosphoserineBy similarity1
Modified residuei317PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylated. Phosphorylation at serine and/or threonine residues occurs in a p38 MAPK- and MAPKAPK2-dependent manner. Phosphorylated by MAPKAPK2 at Ser-53 and Ser-179; phosphorylation increases its stability and cytoplasmic localization, promotes binding to 14-3-3 adapter proteins and inhibits the recruitment of cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to the mRNA decay machinery, thereby inhibiting ZFP36-induced ARE-containing mRNA deadenylation and decay processes. Phosphorylation by MAPKAPK2 does not impair ARE-containing RNA-binding. Phosphorylated in a MAPKAPK2- and p38 MAPK-dependent manner upon skeletal muscle satellite cell activation; this phosphorylation inhibits ZFP36-mediated mRNA decay activity, and hence stabilizes MYOD1 mRNA. Phosphorylated by MAPK1 upon mitogen stimulation. Phosphorylated at Ser-59 and Ser-86; these phosphorylations increase in a SH3KBP1-dependent manner. Phosphorylated at serine and threonine residues in a pyruvate kinase PKM- and p38 MAPK-dependent manner. Phosphorylation at Ser-53 may participate in the PKM-mediated degradation of ZFP36 in a p38 MAPK-dependent manner. Dephosphorylated by serine/threonine phosphatase 2A at Ser-179.By similarity
Ubiquitinated; pyruvate kinase (PKM)-dependent ubiquitination leads to proteasomal degradation through a p38 MAPK signaling pathway.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP47973.
PRIDEiP47973.

PTM databases

PhosphoSitePlusiP47973.

Expressioni

Gene expression databases

BgeeiENSRNOG00000019673.

Interactioni

Subunit structurei

Associates with cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to trigger ARE-containing mRNA deadenylation and decay processes. Part of a mRNA decay activation complex at least composed of poly(A)-specific exoribonucleases CNOT6, EXOSC2 and XRN1 and mRNA-decapping enzymes DCP1A and DCP2. Associates with the RNA exosome complex. Interacts (via phosphorylated form) with 14-3-3 proteins; these interactions promote exclusion of ZFP36 from cytoplasmic stress granules in response to arsenite treatment in a MAPKAPK2-dependent manner and does not prevent CCR4-NOT deadenylase complex recruitment or ZFP36-induced ARE-containing mRNA deadenylation and decay processes. Interacts with 14-3-3 proteins; these interactions occur in response to rapamycin in an Akt-dependent manner. Interacts with AGO2 and AGO4. Interacts (via C-terminus) with CNOT1; this interaction occurs in a RNA-independent manner and induces mRNA deadenylation. Interacts (via N-terminus) with CNOT6. Interacts with CNOT6L. Interacts (via C-terminus) with CNOT7; this interaction occurs in a RNA-independent manner, induces mRNA deadenylation and is inhibited in a phosphorylation MAPKAPK2-dependent manner. Interacts (via unphosphorylated form) with CNOT8; this interaction occurs in a RNA-independent manner and is inhibited in a phosphorylation MAPKAPK2-dependent manner. Interacts with DCP1A. Interacts (via N-terminus) with DCP2. Interacts with EDC3. Interacts (via N-terminus) with EXOSC2. Interacts with heat shock 70 kDa proteins. Interacts with KHSRP; this interaction increases upon cytokine-induced treatment. Interacts with MAP3K4; this interaction enhances the association with SH3KBP1/CIN85. Interacts with MAPKAPK2; this interaction occurs upon skeletal muscle satellite cell activation. Interacts with NCL. Interacts with NUP214; this interaction increases upon lipopolysaccharide (LPS) stimulation. Interacts with PABPC1; this interaction occurs in a RNA-dependent manner. Interacts (via hypophosphorylated form) with PABPN1 (via RRM domain and C-terminal arginine-rich region); this interaction occurs in the nucleus in a RNA-independent manner, decreases in presence of single-stranded poly(A) RNA-oligomer and in a p38 MAPK-dependent-manner and inhibits nuclear poly(A) tail synthesis. Interacts with PAN2. Interacts (via C3H1-type zinc finger domains) with PKM. Interacts (via C3H1-type zinc finger domains) with nuclear RNA poly(A) polymerase. Interacts with PPP2CA; this interaction occurs in LPS-stimulated cells and induces ZFP36 dephosphorylation, and hence may promote ARE-containing mRNAs decay. Interacts (via C-terminus) with PRR5L (via C-terminus); this interaction may accelerate ZFP36-mediated mRNA decay during stress. Interacts (via C-terminus) with SFN; this interaction occurs in a phosphorylation-dependent manner. Interacts (via extreme C-terminal region) with SH3KBP1/CIN85 (via SH3 domains); this interaction enhances MAP3K4-induced phosphorylation of ZFP36 at Ser-59 and Ser-86 and does not alter neither ZFP36 binding to ARE-containing transcripts nor TNF-alpha mRNA decay. Interacts with XRN1. Interacts (via C-terminus and Ser-179 phosphorylated form) with YWHAB; this interaction occurs in a p38/MAPKAPK2-dependent manner, increases cytoplasmic localization of ZFP36 and protects ZFP36 from Ser-179 dephosphorylation by serine/threonine phosphatase 2A, and hence may be crucial for stabilizing ARE-containing mRNAs. Interacts (via phosphorylated form) with YWHAE. Interacts (via C-terminus) with YWHAG; this interaction occurs in a phosphorylation-dependent manner. Interacts with YWHAH; this interaction occurs in a phosphorylation-dependent manner. Interacts with YWHAQ; this interaction occurs in a phosphorylation-dependent manner. Interacts with (via C-terminus) YWHAZ; this interaction occurs in a phosphorylation-dependent manner. Does not interact with SH3KBP1.By similarity

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000026661.

Structurei

3D structure databases

ProteinModelPortaliP47973.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati64 – 68P-P-P-P-G5
Repeati191 – 195P-P-P-P-G5
Repeati212 – 216P-P-P-P-G5

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 167Necessary for localization of ARE-containing mRNAs to processing bodies (PBs)By similarityAdd BLAST167
Regioni1 – 93Necessary and sufficient for the association with mRNA decay enzymes and mRNA decay activationBy similarityAdd BLAST93
Regioni1 – 15Necessary for nuclear export1 PublicationAdd BLAST15
Regioni88 – 161Necessary for nuclear localization1 PublicationAdd BLAST74
Regioni90 – 166Necessary for RNA-bindingBy similarityAdd BLAST77
Regioni93 – 320Necessary for localization of ARE-containing mRNAs to processing bodies (PBs)By similarityAdd BLAST228
Regioni96 – 187Necessary for interaction with PABPN1By similarityAdd BLAST92
Regioni167 – 320Necessary for mRNA decay activationBy similarityAdd BLAST154
Regioni306 – 320Interaction with CNOT1By similarityAdd BLAST15

Domaini

The C3H1-type zinc finger domains are necessary for ARE-binding activity.By similarity

Sequence similaritiesi

Contains 2 C3H1-type zinc fingers.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri96 – 124C3H1-type 1PROSITE-ProRule annotationAdd BLAST29
Zinc fingeri134 – 162C3H1-type 2PROSITE-ProRule annotationAdd BLAST29

Keywords - Domaini

Repeat, Zinc-finger

Phylogenomic databases

eggNOGiKOG1677. Eukaryota.
COG5063. LUCA.
HOGENOMiHOG000233479.
HOVERGENiHBG008483.
InParanoidiP47973.
KOiK15308.
PhylomeDBiP47973.

Family and domain databases

Gene3Di4.10.1000.10. 2 hits.
InterProiIPR000571. Znf_CCCH.
[Graphical view]
PfamiPF00642. zf-CCCH. 2 hits.
[Graphical view]
SMARTiSM00356. ZnF_C3H1. 2 hits.
[Graphical view]
SUPFAMiSSF90229. SSF90229. 2 hits.
PROSITEiPS50103. ZF_C3H1. 2 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P47973-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDLSAIYESL MSMSHDLSPD HGGTESSGGL WNINSSDSIP SGVTSRLTGR
60 70 80 90 100
STSLVEGRSC SWVPPPPGFA PLAPRPGPEL SPSPTSPTAT PTTSSRYKTE
110 120 130 140 150
LCRTYSESGR CRYGAKCQFA HGPGELRQAN RHPKYKTELC HKFYLQGRCP
160 170 180 190 200
YGSRCHFIHN PTEDLALPGQ PHVLRQSISF SGLPSGRRTS PPPPGFSGPS
210 220 230 240 250
LSSCSFSPSS SPPPPGDLPL SPSAFSAAPG TPVSRRDPTP ACCPSCRRST
260 270 280 290 300
TPSTIWGPLG GLARSPSAHS LGSDPDDYAS SGSSLGGSDS PVFEAGVFGP
310 320
PQPPAPPRRL PIFNRISVSE
Length:320
Mass (Da):33,654
Last modified:October 1, 1996 - v1
Checksum:iCFC597F3C7E5CA76
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X63369 mRNA. Translation: CAA44970.1.
AB025017 Genomic DNA. Translation: BAB12432.1.
BC060308 mRNA. Translation: AAH60308.1.
PIRiJC1255.
RefSeqiNP_579824.2. NM_133290.3.
UniGeneiRn.82737.

Genome annotation databases

GeneIDi79426.
KEGGirno:79426.
UCSCiRGD:620722. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X63369 mRNA. Translation: CAA44970.1.
AB025017 Genomic DNA. Translation: BAB12432.1.
BC060308 mRNA. Translation: AAH60308.1.
PIRiJC1255.
RefSeqiNP_579824.2. NM_133290.3.
UniGeneiRn.82737.

3D structure databases

ProteinModelPortaliP47973.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000026661.

PTM databases

PhosphoSitePlusiP47973.

Proteomic databases

PaxDbiP47973.
PRIDEiP47973.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi79426.
KEGGirno:79426.
UCSCiRGD:620722. rat.

Organism-specific databases

CTDi7538.
RGDi620722. Zfp36.

Phylogenomic databases

eggNOGiKOG1677. Eukaryota.
COG5063. LUCA.
HOGENOMiHOG000233479.
HOVERGENiHBG008483.
InParanoidiP47973.
KOiK15308.
PhylomeDBiP47973.

Miscellaneous databases

PROiP47973.

Gene expression databases

BgeeiENSRNOG00000019673.

Family and domain databases

Gene3Di4.10.1000.10. 2 hits.
InterProiIPR000571. Znf_CCCH.
[Graphical view]
PfamiPF00642. zf-CCCH. 2 hits.
[Graphical view]
SMARTiSM00356. ZnF_C3H1. 2 hits.
[Graphical view]
SUPFAMiSSF90229. SSF90229. 2 hits.
PROSITEiPS50103. ZF_C3H1. 2 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTTP_RAT
AccessioniPrimary (citable) accession number: P47973
Secondary accession number(s): Q54AH1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: November 30, 2016
This is version 125 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.