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ZFP36 (P26651) - Overview - Molecular Target Synopsis

Protein


ZFP36, mRNA decay activator protein ZFP36
UniProt P26651

Also Known as TTP_HUMAN, ZFP36, G0S24, NUP475, RNF162A, TIS11A, TTP

Zinc-finger RNA-binding protein that destabilizes several 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:9703499, PubMed:10330172, PubMed:10751406, PubMed:11279239, PubMed:12115244, PubMed:12748283, PubMed:15187101, PubMed:15634918, PubMed:17030620, PubMed:16702957, PubMed:20702587, PubMed:20221403, PubMed:21775632, PubMed:27193233, PubMed:23644599, PubMed:25815583). Acts as an 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery (PubMed:15687258, PubMed:23644599). Recruits deadenylase CNOT7 (and probably the CCR4-NOT complex) via association with CNOT1, and hence promotes ARE-mediated mRNA deadenylation (PubMed:23644599). Functions also by recruiting components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs (PubMed:11719186, PubMed:12748283, PubMed:15687258, PubMed:16364915). Self regulates by destabilizing its own mRNA (PubMed:15187101). Binds to 3'-UTR ARE of numerous mRNAs and of its own mRNA (PubMed:10330172, PubMed:10751406, PubMed:12115244, PubMed:15187101, PubMed:15634918, PubMed:17030620, PubMed:16702957, PubMed:19188452, PubMed:20702587, PubMed:20221403, PubMed:21775632, PubMed:25815583). 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 (By similarity). 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 (PubMed:18367721). Promotes ARE-mediated mRNA decay of hypoxia-inducible factor HIF1A mRNA during the response of endothelial cells to hypoxia (PubMed:21775632). Positively regulates early adipogenesis of preadipocytes by promoting ARE-mediated mRNA decay of immediate early genes (IEGs) (By similarity). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA (PubMed:20702587). Plays a role in maintaining skeletal muscle satellite cell quiescence by promoting ARE-mediated mRNA decay of the myogenic determination factor MYOD1 mRNA (By similarity). Associates also with and regulates the expression of non-ARE-containing target mRNAs at the post-transcriptional level, such as MHC class I mRNAs (PubMed:18367721). Participates in association with argonaute RISC catalytic components in the ARE-mediated mRNA decay mechanism; assists microRNA (miRNA) targeting ARE-containing mRNAs (PubMed:15766526). May also play a role in the regulation of cytoplasmic mRNA decapping; enhances decapping of ARE-containing RNAs, in vitro (PubMed:16364915). Involved in the delivery of target ARE-mRNAs to processing bodies (PBs) (PubMed:17369404). In addition to its cytosolic mRNA-decay function, affects nuclear pre-mRNA processing (By similarity). Negatively regulates nuclear poly(A)-binding protein PABPN1-stimulated polyadenylation activity on ARE-containing pre-mRNA during LPS-stimulated macrophages (By similarity). Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion (By similarity). Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis (PubMed:27182009). Plays a role as a tumor suppressor by inhibiting cell proliferation in breast cancer cells (PubMed:26926077)., (Microbial infection) Negatively regulates HTLV-1 TAX-dependent transactivation of viral long terminal repeat (LTR) promoter. Associates with cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to trigger ARE-containing mRNA deadenylation and decay processes (By similarity). 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 (PubMed:15687258). Associates with the RNA exosome complex (PubMed:11719186). 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 (By similarity). Interacts with 14-3-3 proteins; these interactions occur in response to rapamycin in an Akt-dependent manner (PubMed:16702957). Interacts with AGO2 and AGO4 (PubMed:15766526). Interacts (via C-terminus) with CNOT1; this interaction occurs in a RNA-independent manner and induces mRNA deadenylation (PubMed:23644599). Interacts (via N-terminus) with CNOT6 (PubMed:15687258). Interacts with CNOT6L (By similarity). 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 (PubMed:25106868). Interacts (via unphosphorylated form) with CNOT8; this interaction occurs in a RNA-independent manner and is inhibited in a phosphorylation MAPKAPK2-dependent manner (By similarity). Interacts with DCP1A (PubMed:15687258). Interacts (via N-terminus) with DCP2 (PubMed:15687258, PubMed:16364915). Interacts with EDC3 (PubMed:16364915). Interacts (via N-terminus) with EXOSC2 (PubMed:15687258). Interacts with heat shock 70 kDa proteins (PubMed:20221403). Interacts with KHSRP; this interaction increases upon cytokine-induced treatment (PubMed:16126846). Interacts with MAP3K4; this interaction enhances the association with SH3KBP1/CIN85 (PubMed:20221403). Interacts with MAPKAPK2; this interaction occurs upon skeletal muscle satellite cell activation (By similarity). Interacts with NCL (PubMed:20221403). Interacts with NUP214; this interaction increases upon lipopolysaccharide (LPS) stimulation (PubMed:14766228). Interacts with PABPC1; this interaction occurs in a RNA-dependent manner (PubMed:20221403). 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 (By similarity). Interacts with PAN2 (By similarity). Interacts (via C3H1-type zinc finger domains) with PKM (PubMed:26926077). Interacts (via C3H1-type zinc finger domains) with nuclear RNA poly(A) polymerase (By similarity). Interacts with PPP2CA; this interaction occurs in LPS-stimulated cells and induces ZFP36 dephosphorylation, and hence may promote ARE-containing mRNAs decay (By similarity). Interacts (via C-terminus) with PRR5L (via C-terminus); this interaction may accelerate ZFP36-mediated mRNA decay during stress (PubMed:21964062). Interacts (via C-terminus) with SFN; this interaction occurs in a phosphorylation-dependent manner (By similarity). Interacts (via extreme C-terminal region) with SH3KBP1/CIN85 (via SH3 domains); this interaction enhances MAP3K4-induced phosphorylation of ZFP36 at Ser-66 and Ser-93 and does not alter neither ZFP36 binding to ARE-containing transcripts nor TNF-alpha mRNA decay (PubMed:20221403). Interacts with XRN1 (PubMed:15687258). Interacts (via C-terminus and Ser-186 phosphorylated form) with YWHAB; this interaction occurs in a p38/MAPKAPK2-dependent manner, increases cytoplasmic localization of ZFP36 and protects ZFP36 from Ser-186 dephosphorylation by serine/threonine phosphatase 2A, and hence may be crucial for stabilizing ARE-containing mRNAs (By si

4J8S
12 RESIDUE FRAGMENT OF
TRISTETRAPROLIN
IN THE STRUCTURE OF
CRYSTAL STRUCTURE OF HUMAN CNOT1 MIF4G DOMAIN IN COMPLEX WITH A TTP PEPTIDE
RCSB/PDB
Inspect Structure
See all 3D Structures for ZFP36

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: ZFP36 is active in the following subcellular-locations: cytoplasm, cytoplasmic granule, nucleus, p-body.
GO terms: ZFP36 is active in the following subcellular-locations: cytoplasm, cytoplasmic stress granule, cytosol, nucleus, P-body, ribonucleoprotein complex.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project ZFP36 has gain in 15 cell-lines, loss in 1 cell-lines and no signal in 988 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: SR, OVCAR_3, KM12

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: PANC-1, MOLP-2, SNU-620

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, A549, IMR-90

(see details)

3D Structures


For ZFP36 there are:
1 structures (1 chains) solved
0 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


ZFP36 has been screened with compounds ( bioactivities). (see details)