ID TTP_RAT Reviewed; 320 AA. AC P47973; Q54AH1; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 08-MAY-2019, entry version 137. DE RecName: Full=mRNA decay activator protein ZFP36 {ECO:0000305}; DE AltName: Full=TPA-induced sequence 11 {ECO:0000250|UniProtKB:P22893}; DE AltName: Full=Tristetraprolin {ECO:0000250|UniProtKB:P26651}; DE AltName: Full=Zinc finger protein 36 {ECO:0000312|RGD:620722}; DE Short=Zfp-36 {ECO:0000250|UniProtKB:P22893}; GN Name=Zfp36 {ECO:0000312|RGD:620722}; GN Synonyms=Tis11 {ECO:0000303|PubMed:1511903}, GN Ttp {ECO:0000250|UniProtKB:P26651}; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; OC Muroidea; Muridae; Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=1511903; DOI=10.1016/0378-1119(92)90202-Z; RA Kaneda N., Oshima M., Chung S.Y., Guroff G.; RT "Sequence of a rat TIS11 cDNA, an immediate early gene induced by RT growth factors and phorbol esters."; RL Gene 118:289-291(1992). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=11129950; DOI=10.1023/A:1007172316657; RA Kaneda N., Murata T., Niimi Y., Minamiyama M.; RT "Cloning and characterization of the rat TIS11 gene."; RL Mol. Cell. Biochem. 213:119-126(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Pituitary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP SUBCELLULAR LOCATION, MUTAGENESIS OF LEU-3 AND LEU-10, AND DOMAIN. RX PubMed=12054509; DOI=10.1016/S0006-291X(02)00363-7; RA Murata T., Yoshino Y., Morita N., Kaneda N.; RT "Identification of nuclear import and export signals within the RT structure of the zinc finger protein TIS11."; RL Biochem. Biophys. Res. Commun. 293:1242-1247(2002). RN [5] RP RNA-BINDING. RX PubMed=27193233; DOI=10.1007/s00726-016-2261-9; RA Nowotarski S.L., Origanti S., Sass-Kuhn S., Shantz L.M.; RT "Destabilization of the ornithine decarboxylase mRNA transcript by the RT RNA-binding protein tristetraprolin."; RL Amino Acids 48:2303-2311(2016). CC -!- FUNCTION: Zinc-finger RNA-binding protein that destabilizes CC numerous cytoplasmic AU-rich element (ARE)-containing mRNA CC transcripts by promoting their poly(A) tail removal or CC deadenylation, and hence provide a mechanism for attenuating CC protein synthesis (PubMed:27193233). Acts as an 3'-untranslated CC region (UTR) ARE mRNA-binding adapter protein to communicate CC signaling events to the mRNA decay machinery. Recruits deadenylase CC CNOT7 (and probably the CCR4-NOT complex) via association with CC CNOT1, and hence promotes ARE-mediated mRNA deadenylation. CC Functions also by recruiting components of the cytoplasmic RNA CC decay machinery to the bound ARE-containing mRNAs. Self regulates CC by destabilizing its own mRNA (By similarity). Binds to 3'-UTR ARE CC of numerous mRNAs (PubMed:27193233). Binds also to ARE of its own CC mRNA. Plays a role in anti-inflammatory responses; suppresses CC tumor necrosis factor (TNF)-alpha production by stimulating ARE- CC mediated TNF-alpha mRNA decay and several other inflammatory ARE- CC containing mRNAs in interferon (IFN)- and/or lipopolysaccharide CC (LPS)-induced macrophages. Plays also a role in the regulation of CC dendritic cell maturation at the post-transcriptional level, and CC hence operates as part of a negative feedback loop to limit the CC inflammatory response. Promotes ARE-mediated mRNA decay of CC hypoxia-inducible factor HIF1A mRNA during the response of CC endothelial cells to hypoxia. Positively regulates early CC adipogenesis of preadipocytes by promoting ARE-mediated mRNA decay CC of immediate early genes (IEGs). Negatively regulates CC hematopoietic/erythroid cell differentiation by promoting ARE- CC mediated mRNA decay of the transcription factor STAT5B mRNA. Plays CC a role in maintaining skeletal muscle satellite cell quiescence by CC promoting ARE-mediated mRNA decay of the myogenic determination CC factor MYOD1 mRNA. Associates also with and regulates the CC expression of non-ARE-containing target mRNAs at the post- CC transcriptional level, such as MHC class I mRNAs. Participates in CC association with argonaute RISC catalytic components in the ARE- CC mediated mRNA decay mechanism; assists microRNA (miRNA) targeting CC ARE-containing mRNAs. May also play a role in the regulation of CC cytoplasmic mRNA decapping; enhances decapping of ARE-containing CC RNAs, in vitro. Involved in the delivery of target ARE-mRNAs to CC processing bodies (PBs). In addition to its cytosolic mRNA-decay CC function, affects nuclear pre-mRNA processing. Negatively CC regulates nuclear poly(A)-binding protein PABPN1-stimulated CC polyadenylation activity on ARE-containing pre-mRNA during LPS- CC stimulated macrophages. Also involved in the regulation of stress CC granule (SG) and P-body (PB) formation and fusion. Plays a role in CC the regulation of keratinocyte proliferation, differentiation and CC apoptosis. Plays a role as a tumor suppressor by inhibiting cell CC proliferation in breast cancer cells (By similarity). CC {ECO:0000250|UniProtKB:P22893, ECO:0000250|UniProtKB:P26651, CC ECO:0000269|PubMed:27193233}. CC -!- SUBUNIT: Associates with cytoplasmic CCR4-NOT and PAN2-PAN3 CC deadenylase complexes to trigger ARE-containing mRNA deadenylation CC and decay processes. Part of a mRNA decay activation complex at CC least composed of poly(A)-specific exoribonucleases CNOT6, EXOSC2 CC and XRN1 and mRNA-decapping enzymes DCP1A and DCP2. Associates CC with the RNA exosome complex. Interacts (via phosphorylated form) CC with 14-3-3 proteins; these interactions promote exclusion of CC ZFP36 from cytoplasmic stress granules in response to arsenite CC treatment in a MAPKAPK2-dependent manner and does not prevent CC CCR4-NOT deadenylase complex recruitment or ZFP36-induced ARE- CC containing mRNA deadenylation and decay processes. Interacts with CC 14-3-3 proteins; these interactions occur in response to rapamycin CC in an Akt-dependent manner. Interacts with AGO2 and AGO4. CC Interacts (via C-terminus) with CNOT1; this interaction occurs in CC a RNA-independent manner and induces mRNA deadenylation. Interacts CC (via N-terminus) with CNOT6. Interacts with CNOT6L. Interacts (via CC C-terminus) with CNOT7; this interaction occurs in a RNA- CC independent manner, induces mRNA deadenylation and is inhibited in CC a phosphorylation MAPKAPK2-dependent manner. Interacts (via CC unphosphorylated form) with CNOT8; this interaction occurs in a CC RNA-independent manner and is inhibited in a phosphorylation CC MAPKAPK2-dependent manner. Interacts with DCP1A. Interacts (via N- CC terminus) with DCP2. Interacts with EDC3. Interacts (via N- CC terminus) with EXOSC2. Interacts with heat shock 70 kDa proteins. CC Interacts with KHSRP; this interaction increases upon cytokine- CC induced treatment. Interacts with MAP3K4; this interaction CC enhances the association with SH3KBP1/CIN85. Interacts with CC MAPKAPK2; this interaction occurs upon skeletal muscle satellite CC cell activation. Interacts with NCL. Interacts with NUP214; this CC interaction increases upon lipopolysaccharide (LPS) stimulation. CC Interacts with PABPC1; this interaction occurs in a RNA-dependent CC manner. Interacts (via hypophosphorylated form) with PABPN1 (via CC RRM domain and C-terminal arginine-rich region); this interaction CC occurs in the nucleus in a RNA-independent manner, decreases in CC presence of single-stranded poly(A) RNA-oligomer and in a p38 CC MAPK-dependent-manner and inhibits nuclear poly(A) tail synthesis. CC Interacts with PAN2. Interacts (via C3H1-type zinc finger domains) CC with PKM. Interacts (via C3H1-type zinc finger domains) with CC nuclear RNA poly(A) polymerase. Interacts with PPP2CA; this CC interaction occurs in LPS-stimulated cells and induces ZFP36 CC dephosphorylation, and hence may promote ARE-containing mRNAs CC decay. Interacts (via C-terminus) with PRR5L (via C-terminus); CC this interaction may accelerate ZFP36-mediated mRNA decay during CC stress. Interacts (via C-terminus) with SFN; this interaction CC occurs in a phosphorylation-dependent manner. Interacts (via CC extreme C-terminal region) with SH3KBP1/CIN85 (via SH3 domains); CC this interaction enhances MAP3K4-induced phosphorylation of ZFP36 CC at Ser-59 and Ser-86 and does not alter neither ZFP36 binding to CC ARE-containing transcripts nor TNF-alpha mRNA decay. Interacts CC with XRN1. Interacts (via C-terminus and Ser-179 phosphorylated CC form) with YWHAB; this interaction occurs in a p38/MAPKAPK2- CC dependent manner, increases cytoplasmic localization of ZFP36 and CC protects ZFP36 from Ser-179 dephosphorylation by serine/threonine CC phosphatase 2A, and hence may be crucial for stabilizing ARE- CC containing mRNAs. Interacts (via phosphorylated form) with YWHAE. CC Interacts (via C-terminus) with YWHAG; this interaction occurs in CC a phosphorylation-dependent manner. Interacts with YWHAH; this CC interaction occurs in a phosphorylation-dependent manner. CC Interacts with YWHAQ; this interaction occurs in a CC phosphorylation-dependent manner. Interacts with (via C-terminus) CC YWHAZ; this interaction occurs in a phosphorylation-dependent CC manner. Does not interact with SH3KBP1. Interacts (via P-P-P-P-G CC repeats) with GIGYF2; the interaction is direct (By similarity). CC {ECO:0000250|UniProtKB:P22893, ECO:0000250|UniProtKB:P26651}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12054509}. CC Cytoplasm {ECO:0000269|PubMed:12054509}. Cytoplasmic granule CC {ECO:0000250|UniProtKB:P22893}. Cytoplasm, P-body CC {ECO:0000250|UniProtKB:P22893}. Note=Shuttles between nucleus and CC cytoplasm in a CRM1-dependent manner (PubMed:12054509). Localized CC predominantly in the cytoplasm in a p38 MAPK- and YWHAB-dependent CC manner. Colocalizes with SH3KBP1 and MAP3K4 in the cytoplasm. CC Component of cytoplasmic stress granules (SGs). Localizes to CC cytoplasmic stress granules upon energy starvation. Localizes in CC processing bodies (PBs). Excluded from stress granules in a CC phosphorylation MAPKAPK2-dependent manner. Shuttles in and out of CC both cytoplasmic P-body and SGs (By similarity). CC {ECO:0000250|UniProtKB:P22893, ECO:0000250|UniProtKB:P26651, CC ECO:0000269|PubMed:12054509}. CC -!- DOMAIN: The C3H1-type zinc finger domains are necessary for ARE- CC binding activity. {ECO:0000250|UniProtKB:P26651}. CC -!- PTM: Phosphorylated. Phosphorylation at serine and/or threonine CC residues occurs in a p38 MAPK- and MAPKAPK2-dependent manner. CC Phosphorylated by MAPKAPK2 at Ser-53 and Ser-179; phosphorylation CC increases its stability and cytoplasmic localization, promotes CC binding to 14-3-3 adapter proteins and inhibits the recruitment of CC cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to the CC mRNA decay machinery, thereby inhibiting ZFP36-induced ARE- CC containing mRNA deadenylation and decay processes. Phosphorylation CC by MAPKAPK2 does not impair ARE-containing RNA-binding. CC Phosphorylated in a MAPKAPK2- and p38 MAPK-dependent manner upon CC skeletal muscle satellite cell activation; this phosphorylation CC inhibits ZFP36-mediated mRNA decay activity, and hence stabilizes CC MYOD1 mRNA. Phosphorylated by MAPK1 upon mitogen stimulation. CC Phosphorylated at Ser-59 and Ser-86; these phosphorylations CC increase in a SH3KBP1-dependent manner. Phosphorylated at serine CC and threonine residues in a pyruvate kinase PKM- and p38 MAPK- CC dependent manner. Phosphorylation at Ser-53 may participate in the CC PKM-mediated degradation of ZFP36 in a p38 MAPK-dependent manner. CC Dephosphorylated by serine/threonine phosphatase 2A at Ser-179. CC {ECO:0000250|UniProtKB:P22893, ECO:0000250|UniProtKB:P26651}. CC -!- PTM: Ubiquitinated; pyruvate kinase (PKM)-dependent ubiquitination CC leads to proteasomal degradation through a p38 MAPK signaling CC pathway. {ECO:0000250|UniProtKB:P26651}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X63369; CAA44970.1; -; mRNA. DR EMBL; AB025017; BAB12432.1; -; Genomic_DNA. DR EMBL; BC060308; AAH60308.1; -; mRNA. DR PIR; JC1255; JC1255. DR RefSeq; NP_579824.2; NM_133290.3. DR SMR; P47973; -. DR STRING; 10116.ENSRNOP00000026661; -. DR PhosphoSitePlus; P47973; -. DR PaxDb; P47973; -. DR PRIDE; P47973; -. DR GeneID; 79426; -. DR KEGG; rno:79426; -. DR UCSC; RGD:620722; rat. DR CTD; 7538; -. DR RGD; 620722; Zfp36. DR eggNOG; KOG1677; Eukaryota. DR eggNOG; COG5063; LUCA. DR HOGENOM; HOG000233479; -. DR InParanoid; P47973; -. DR KO; K15308; -. DR OrthoDB; 1541140at2759; -. DR PhylomeDB; P47973; -. DR Reactome; R-RNO-450513; Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA. DR PRO; PR:P47973; -. DR Proteomes; UP000002494; Unplaced. DR GO; GO:0005737; C:cytoplasm; IDA:RGD. DR GO; GO:0010494; C:cytoplasmic stress granule; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; IBA:GO_Central. DR GO; GO:0005634; C:nucleus; IDA:RGD. DR GO; GO:0000932; C:P-body; ISS:UniProtKB. DR GO; GO:1990904; C:ribonucleoprotein complex; ISS:UniProtKB. DR GO; GO:0071889; F:14-3-3 protein binding; ISS:UniProtKB. DR GO; GO:0017091; F:AU-rich element binding; ISS:UniProtKB. DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW. DR GO; GO:0031072; F:heat shock protein binding; ISS:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0035925; F:mRNA 3'-UTR AU-rich region binding; ISS:UniProtKB. DR GO; GO:0003730; F:mRNA 3'-UTR binding; IDA:UniProtKB. DR GO; GO:0070063; F:RNA polymerase binding; ISS:UniProtKB. DR GO; GO:0061158; P:3'-UTR-mediated mRNA destabilization; ISS:UniProtKB. DR GO; GO:0070935; P:3'-UTR-mediated mRNA stabilization; ISS:UniProtKB. DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; ISS:UniProtKB. DR GO; GO:0044344; P:cellular response to fibroblast growth factor stimulus; ISS:UniProtKB. DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; ISS:UniProtKB. DR GO; GO:0097011; P:cellular response to granulocyte macrophage colony-stimulating factor stimulus; ISS:UniProtKB. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; ISS:UniProtKB. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; ISS:UniProtKB. DR GO; GO:0000165; P:MAPK cascade; ISS:UniProtKB. DR GO; GO:0035278; P:miRNA mediated inhibition of translation; ISS:UniProtKB. DR GO; GO:0006402; P:mRNA catabolic process; ISS:UniProtKB. DR GO; GO:0051028; P:mRNA transport; ISS:UniProtKB. DR GO; GO:0007275; P:multicellular organism development; IEA:UniProtKB-KW. DR GO; GO:0045647; P:negative regulation of erythrocyte differentiation; ISS:UniProtKB. DR GO; GO:0045085; P:negative regulation of interleukin-2 biosynthetic process; ISS:UniProtKB. DR GO; GO:1904246; P:negative regulation of polynucleotide adenylyltransferase activity; ISS:UniProtKB. DR GO; GO:0032897; P:negative regulation of viral transcription; ISS:UniProtKB. DR GO; GO:0031086; P:nuclear-transcribed mRNA catabolic process, deadenylation-independent decay; ISS:UniProtKB. DR GO; GO:0038066; P:p38MAPK cascade; ISS:UniProtKB. DR GO; GO:1901835; P:positive regulation of deadenylation-independent decapping of nuclear-transcribed mRNA; ISS:UniProtKB. DR GO; GO:0045600; P:positive regulation of fat cell differentiation; ISS:UniProtKB. DR GO; GO:2000637; P:positive regulation of gene silencing by miRNA; ISS:UniProtKB. DR GO; GO:1904582; P:positive regulation of intracellular mRNA localization; ISS:UniProtKB. DR GO; GO:0061014; P:positive regulation of mRNA catabolic process; ISS:UniProtKB. DR GO; GO:1900153; P:positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay; ISS:UniProtKB. DR GO; GO:0060213; P:positive regulation of nuclear-transcribed mRNA poly(A) tail shortening; ISS:UniProtKB. DR GO; GO:1902172; P:regulation of keratinocyte apoptotic process; ISS:UniProtKB. DR GO; GO:0045616; P:regulation of keratinocyte differentiation; ISS:UniProtKB. DR GO; GO:0010837; P:regulation of keratinocyte proliferation; ISS:UniProtKB. DR GO; GO:0043488; P:regulation of mRNA stability; ISS:UniProtKB. DR GO; GO:0032680; P:regulation of tumor necrosis factor production; ISS:UniProtKB. DR GO; GO:0042594; P:response to starvation; ISS:UniProtKB. DR GO; GO:0009611; P:response to wounding; ISS:UniProtKB. DR InterPro; IPR000571; Znf_CCCH. DR InterPro; IPR036855; Znf_CCCH_sf. DR Pfam; PF00642; zf-CCCH; 2. DR SMART; SM00356; ZnF_C3H1; 2. DR SUPFAM; SSF90229; SSF90229; 2. DR PROSITE; PS50103; ZF_C3H1; 2. PE 1: Evidence at protein level; KW Complete proteome; Cytoplasm; Developmental protein; DNA-binding; KW Exosome; Metal-binding; mRNA transport; Nucleus; Phosphoprotein; KW Reference proteome; Repeat; Ribonucleoprotein; Transport; KW Ubl conjugation; Zinc; Zinc-finger. FT CHAIN 1 320 mRNA decay activator protein ZFP36. FT /FTId=PRO_0000089165. FT REPEAT 64 68 P-P-P-P-G. FT REPEAT 191 195 P-P-P-P-G. FT REPEAT 212 216 P-P-P-P-G. FT ZN_FING 96 124 C3H1-type 1. {ECO:0000255|PROSITE- FT ProRule:PRU00723}. FT ZN_FING 134 162 C3H1-type 2. {ECO:0000255|PROSITE- FT ProRule:PRU00723}. FT REGION 1 167 Necessary for localization of ARE- FT containing mRNAs to processing bodies FT (PBs). {ECO:0000250|UniProtKB:P26651}. FT REGION 1 93 Necessary and sufficient for the FT association with mRNA decay enzymes and FT mRNA decay activation. FT {ECO:0000250|UniProtKB:P26651}. FT REGION 1 15 Necessary for nuclear export. FT {ECO:0000269|PubMed:12054509}. FT REGION 88 161 Necessary for nuclear localization. FT {ECO:0000269|PubMed:12054509}. FT REGION 90 166 Necessary for RNA-binding. FT {ECO:0000250|UniProtKB:P26651}. FT REGION 93 320 Necessary for localization of ARE- FT containing mRNAs to processing bodies FT (PBs). {ECO:0000250|UniProtKB:P26651}. FT REGION 96 187 Necessary for interaction with PABPN1. FT {ECO:0000250|UniProtKB:P22893}. FT REGION 167 320 Necessary for mRNA decay activation. FT {ECO:0000250|UniProtKB:P26651}. FT REGION 306 320 Interaction with CNOT1. FT {ECO:0000250|UniProtKB:P26651}. FT MOD_RES 53 53 Phosphoserine; by MAPKAPK2. FT {ECO:0000250|UniProtKB:P22893}. FT MOD_RES 59 59 Phosphoserine. FT {ECO:0000250|UniProtKB:P26651}. FT MOD_RES 81 81 Phosphoserine. FT {ECO:0000250|UniProtKB:P26651}. FT MOD_RES 83 83 Phosphoserine. FT {ECO:0000250|UniProtKB:P22893}. FT MOD_RES 85 85 Phosphothreonine. FT {ECO:0000250|UniProtKB:P26651}. FT MOD_RES 86 86 Phosphoserine. FT {ECO:0000250|UniProtKB:P26651}. FT MOD_RES 179 179 Phosphoserine; by MAPKAPK2. FT {ECO:0000250|UniProtKB:P26651}. FT MOD_RES 190 190 Phosphoserine. FT {ECO:0000250|UniProtKB:P26651}. FT MOD_RES 211 211 Phosphoserine. FT {ECO:0000250|UniProtKB:P26651}. FT MOD_RES 221 221 Phosphoserine; by MAPK1; in vitro. FT {ECO:0000250|UniProtKB:P26651}. FT MOD_RES 251 251 Phosphothreonine. FT {ECO:0000250|UniProtKB:P22893}. FT MOD_RES 270 270 Phosphoserine. FT {ECO:0000250|UniProtKB:P26651}. FT MOD_RES 290 290 Phosphoserine. FT {ECO:0000250|UniProtKB:P26651}. FT MOD_RES 317 317 Phosphoserine. FT {ECO:0000250|UniProtKB:P26651}. FT MUTAGEN 3 3 L->A: Inhibits nucleus export. FT {ECO:0000269|PubMed:12054509}. FT MUTAGEN 10 10 L->A: Inhibits nucleus export. FT {ECO:0000269|PubMed:12054509}. SQ SEQUENCE 320 AA; 33654 MW; CFC597F3C7E5CA76 CRC64; MDLSAIYESL MSMSHDLSPD HGGTESSGGL WNINSSDSIP SGVTSRLTGR STSLVEGRSC SWVPPPPGFA PLAPRPGPEL SPSPTSPTAT PTTSSRYKTE LCRTYSESGR CRYGAKCQFA HGPGELRQAN RHPKYKTELC HKFYLQGRCP YGSRCHFIHN PTEDLALPGQ PHVLRQSISF SGLPSGRRTS PPPPGFSGPS LSSCSFSPSS SPPPPGDLPL SPSAFSAAPG TPVSRRDPTP ACCPSCRRST TPSTIWGPLG GLARSPSAHS LGSDPDDYAS SGSSLGGSDS PVFEAGVFGP PQPPAPPRRL PIFNRISVSE //