4EBP2_MOUSE
ID 4EBP2_MOUSE Reviewed; 120 AA.
AC P70445;
DT 19-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1997, sequence version 1.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=Eukaryotic translation initiation factor 4E-binding protein 2 {ECO:0000250|UniProtKB:Q13542};
DE Short=4E-BP2 {ECO:0000250|UniProtKB:Q13542};
DE Short=eIF4E-binding protein 2 {ECO:0000250|UniProtKB:Q13542};
DE AltName: Full=Phosphorylated heat- and acid-stable protein regulated by insulin 2 {ECO:0000303|PubMed:8939971};
DE Short=PHAS-II {ECO:0000303|PubMed:8939971};
GN Name=Eif4ebp2 {ECO:0000312|MGI:MGI:109198};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RX PubMed=8939971; DOI=10.1074/jbc.271.47.30199;
RA Lin T.A., Lawrence J.C. Jr.;
RT "Control of the translational regulators PHAS-I and PHAS-II by insulin and
RT cAMP in 3T3-L1 adipocytes.";
RL J. Biol. Chem. 271:30199-30204(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=16237163; DOI=10.1523/jneurosci.2423-05.2005;
RA Banko J.L., Poulin F., Hou L., DeMaria C.T., Sonenberg N., Klann E.;
RT "The translation repressor 4E-BP2 is critical for eIF4F complex formation,
RT synaptic plasticity, and memory in the hippocampus.";
RL J. Neurosci. 25:9581-9590(2005).
RN [4]
RP DISRUPTION PHENOTYPE.
RX PubMed=17273556; DOI=10.1172/jci29528;
RA Le Bacquer O., Petroulakis E., Paglialunga S., Poulin F., Richard D.,
RA Cianflone K., Sonenberg N.;
RT "Elevated sensitivity to diet-induced obesity and insulin resistance in
RT mice lacking 4E-BP1 and 4E-BP2.";
RL J. Clin. Invest. 117:387-396(2007).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=17029989; DOI=10.1016/j.nlm.2006.08.012;
RA Banko J.L., Merhav M., Stern E., Sonenberg N., Rosenblum K., Klann E.;
RT "Behavioral alterations in mice lacking the translation repressor 4E-BP2.";
RL Neurobiol. Learn. Mem. 87:248-256(2007).
RN [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=19175792; DOI=10.1111/j.1365-2567.2008.02981.x;
RA Olson K.E., Booth G.C., Poulin F., Sonenberg N., Beretta L.;
RT "Impaired myelopoiesis in mice lacking the repressors of translation
RT initiation, 4E-BP1 and 4E-BP2.";
RL Immunology 128:E376-E384(2009).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37; THR-46; SER-65 AND
RP THR-70, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [8]
RP DEAMIDATION AT ASN-99 AND ASN-102, AND INTERACTION WITH PCMT1.
RX PubMed=20424163; DOI=10.1074/jbc.m110.120774;
RA Bidinosti M., Martineau Y., Frank F., Sonenberg N.;
RT "Repair of isoaspartate formation modulates the interaction of deamidated
RT 4E-BP2 with mTORC1 in brain.";
RL J. Biol. Chem. 285:19402-19408(2010).
RN [9]
RP FUNCTION, DEAMIDATION AT ASN-99 AND ASN-102, PHOSPHORYLATION AT THR-37;
RP THR-46; SER-65 AND THR-70, DOMAIN TOS, INTERACTION WITH RPTOR, AND
RP MUTAGENESIS OF THR-37; THR-46; THR-70; 99-ASN--ASN-102 AND
RP 116-PHE--ILE-120.
RX PubMed=20347422; DOI=10.1016/j.molcel.2010.02.022;
RA Bidinosti M., Ran I., Sanchez-Carbente M.R., Martineau Y., Gingras A.C.,
RA Gkogkas C., Raught B., Bramham C.R., Sossin W.S., Costa-Mattioli M.,
RA DesGroseillers L., Lacaille J.C., Sonenberg N.;
RT "Postnatal deamidation of 4E-BP2 in brain enhances its association with
RT raptor and alters kinetics of excitatory synaptic transmission.";
RL Mol. Cell 37:797-808(2010).
RN [10]
RP FUNCTION, AND PHOSPHORYLATION.
RX PubMed=24139800; DOI=10.1016/j.celrep.2013.09.017;
RA Hartman N.W., Lin T.V., Zhang L., Paquelet G.E., Feliciano D.M., Bordey A.;
RT "mTORC1 targets the translational repressor 4E-BP2, but not S6 kinase 1/2,
RT to regulate neural stem cell self-renewal in vivo.";
RL Cell Rep. 5:433-444(2013).
RN [11]
RP INTERACTION WITH RPTOR.
RX PubMed=23184952; DOI=10.1074/jbc.m112.402461;
RA Dennis M.D., Kimball S.R., Jefferson L.S.;
RT "Mechanistic target of rapamycin complex 1 (mTORC1)-mediated
RT phosphorylation is governed by competition between substrates for
RT interaction with raptor.";
RL J. Biol. Chem. 288:10-19(2013).
RN [12]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23172145; DOI=10.1038/nature11628;
RA Gkogkas C.G., Khoutorsky A., Ran I., Rampakakis E., Nevarko T.,
RA Weatherill D.B., Vasuta C., Yee S., Truitt M., Dallaire P., Major F.,
RA Lasko P., Ruggero D., Nader K., Lacaille J.C., Sonenberg N.;
RT "Autism-related deficits via dysregulated eIF4E-dependent translational
RT control.";
RL Nature 493:371-377(2013).
CC -!- FUNCTION: Repressor of translation initiation involved in synaptic
CC plasticity, learning and memory formation (PubMed:16237163,
CC PubMed:17029989). Regulates EIF4E activity by preventing its assembly
CC into the eIF4F complex: hypophosphorylated form of EIF4EBP2 competes
CC with EIF4G1/EIF4G3 and strongly binds to EIF4E, leading to repress
CC translation. In contrast, hyperphosphorylated form dissociates from
CC EIF4E, allowing interaction between EIF4G1/EIF4G3 and EIF4E, leading to
CC initiation of translation (PubMed:17029989, PubMed:20347422,
CC PubMed:23172145). EIF4EBP2 is enriched in brain and acts as a regulator
CC of synapse activity and neuronal stem cell renewal via its ability to
CC repress translation initiation (PubMed:20347422, PubMed:24139800,
CC PubMed:23172145). Mediates the regulation of protein translation by
CC hormones, growth factors and other stimuli that signal through the MAP
CC kinase and mTORC1 pathways (PubMed:8939971).
CC {ECO:0000250|UniProtKB:Q13542, ECO:0000269|PubMed:16237163,
CC ECO:0000269|PubMed:17029989, ECO:0000269|PubMed:20347422,
CC ECO:0000269|PubMed:23172145, ECO:0000269|PubMed:24139800,
CC ECO:0000269|PubMed:8939971}.
CC -!- SUBUNIT: Hypophosphorylated EIF4EBP2 interacts with EIF4E;
CC phosphorylation of EIF4EBP2 by mTORC1 causes dissociation of the
CC complex allowing EIF4G1/EIF4G3 to bind and consequent initiation of
CC translation. Interacts (via TOS motif) with RPTOR; promoting
CC phosphorylation by mTORC1 (PubMed:20347422, PubMed:23184952). Interacts
CC with PCMT1; required to prevent isoaspartate accumulation and convert
CC isoaspartate to Asp (PubMed:20424163). {ECO:0000250|UniProtKB:Q13542,
CC ECO:0000269|PubMed:20347422, ECO:0000269|PubMed:20424163,
CC ECO:0000269|PubMed:23184952}.
CC -!- TISSUE SPECIFICITY: Enriched in brain. {ECO:0000269|PubMed:16237163}.
CC -!- DOMAIN: The TOS motif mediates interaction with RPTOR, leading to
CC promote phosphorylation by mTORC1 complex.
CC {ECO:0000269|PubMed:20347422}.
CC -!- DOMAIN: Intrinsically disordered protein that undergoes folding upon
CC phosphorylation. Hypophosphorylated form interacts strongly with EIF4E
CC using (1) the YXXXXLPhi motif, that undergoes a disorder-to-helix
CC transition upon binding and (2) the secondary EIF4E binding sites
CC (residues 78-82). Phosphorylation at Thr-37 and Thr-46 induces folding
CC of region encompassing residues from Pro-18 to Arg-62 of into a four-
CC stranded beta-domain that sequesters the helical YXXXXLPhi motif into a
CC buried beta-strand, blocking accessibility to EIF4E. Protein
CC phosphorylated at Thr-37 and Thr-46 is however unstable and subsequent
CC phosphorylation at Ser-65, Thr-70 and Ser-83 is required to stabilize
CC the fold, decreasing affinity for EIF4E by a factor of 4000.
CC {ECO:0000250|UniProtKB:Q13542}.
CC -!- PTM: Phosphorylation at Thr-37, Thr-46, Ser-65, Thr-70 and Ser-83 is
CC mediated by MTOR and corresponds to the hyperphosphorylated form: it
CC abolishes binding to EIF4E by inducing folding of intrinsically
CC disordered regions. First phosphorylated at Thr-37 and Thr-46 by MTOR,
CC inducing folding of region encompassing residues from Pro-18 to Arg-62
CC of into a four-stranded beta-domain that sequesters the helical
CC YXXXXLPhi motif into a partly buried beta-strand, blocking
CC accessibility to EIF4E. Protein phosphorylated at Thr-37 and Thr-46 is
CC however unstable and subsequent phosphorylation at Ser-65, Thr-70 and
CC Ser-83 is required to stabilize the fold, decreasing affinity for EIF4E
CC by a factor of 4000. Phosphorylated in response to insulin, EGF and
CC PDGF. {ECO:0000250|UniProtKB:Q13542, ECO:0000269|PubMed:24139800}.
CC -!- PTM: Deamidated at Asn-99 and Asn-102 to aspartate (Asp) in brain.
CC Deamidation promotes interaction with RPTOR, subsequent phosphorylation
CC by mTORC1 and increased translation, leading to impair kinetics of
CC excitatory synaptic transmission. Deamidation takes place during
CC postnatal development, when the PI3K-Akt-mTOR signaling is reduced,
CC suggesting it acts as a compensatory mechanism to promote translation
CC despite attenuated PI3K-Akt-mTOR signaling in neuron development
CC (PubMed:20347422). Deamidation converts Asn residues into a mixture of
CC Asp and isoaspartate; interactions with PCMT1 is required to prevent
CC isoaspartate accumulation and convert isoaspartate to Asp
CC (PubMed:20424163). {ECO:0000269|PubMed:20347422,
CC ECO:0000269|PubMed:20424163}.
CC -!- DISRUPTION PHENOTYPE: Mice develop normally and are fertile. They
CC however show defects in synaptic plasticity, impaired spatial learning
CC and memory and conditioned fear-associative memory deficits
CC (PubMed:16237163). Mice show behavior defects and autistic-like
CC phenotype, characterized by social interaction deficits, altered
CC communication and repetitive/stereotyped behaviors: they show an
CC increased ratio of excitatory to inhibitory synaptic inputs possibly
CC due to increased translation of neuroligin family proteins
CC (PubMed:17029989, PubMed:23172145). Mice lacking both Eif4ebp1 and
CC Eif4ebp2 display increased their sensitivity to diet-induced obesity
CC (PubMed:17273556). Mice lacking both Eif4ebp1 and Eif4ebp2 show defects
CC in myelopoiesis: mice display an increased number of immature
CC granulocytic precursors, associated with a decreased number of mature
CC granulocytic elements (PubMed:19175792). {ECO:0000269|PubMed:16237163,
CC ECO:0000269|PubMed:17029989, ECO:0000269|PubMed:17273556,
CC ECO:0000269|PubMed:19175792, ECO:0000269|PubMed:23172145}.
CC -!- SIMILARITY: Belongs to the eIF4E-binding protein family. {ECO:0000305}.
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DR EMBL; U75530; AAC52899.1; -; mRNA.
DR EMBL; BC015082; AAH15082.1; -; mRNA.
DR CCDS; CCDS23879.1; -.
DR RefSeq; NP_034254.1; NM_010124.2.
DR RefSeq; XP_017169281.1; XM_017313792.1.
DR RefSeq; XP_017169282.1; XM_017313793.1.
DR AlphaFoldDB; P70445; -.
DR SMR; P70445; -.
DR BioGRID; 199422; 5.
DR DIP; DIP-60124N; -.
DR IntAct; P70445; 1.
DR STRING; 10090.ENSMUSP00000020288; -.
DR iPTMnet; P70445; -.
DR PhosphoSitePlus; P70445; -.
DR EPD; P70445; -.
DR jPOST; P70445; -.
DR PaxDb; P70445; -.
DR PeptideAtlas; P70445; -.
DR PRIDE; P70445; -.
DR ProteomicsDB; 296446; -.
DR Antibodypedia; 29025; 289 antibodies from 29 providers.
DR DNASU; 13688; -.
DR Ensembl; ENSMUST00000020288; ENSMUSP00000020288; ENSMUSG00000020091.
DR Ensembl; ENSMUST00000167087; ENSMUSP00000131952; ENSMUSG00000020091.
DR GeneID; 13688; -.
DR KEGG; mmu:13688; -.
DR UCSC; uc007fga.1; mouse.
DR CTD; 1979; -.
DR MGI; MGI:109198; Eif4ebp2.
DR VEuPathDB; HostDB:ENSMUSG00000020091; -.
DR eggNOG; ENOG502S44S; Eukaryota.
DR GeneTree; ENSGT00940000155342; -.
DR HOGENOM; CLU_111706_0_0_1; -.
DR InParanoid; P70445; -.
DR OMA; NHINNRD; -.
DR OrthoDB; 1597535at2759; -.
DR PhylomeDB; P70445; -.
DR TreeFam; TF101530; -.
DR BioGRID-ORCS; 13688; 3 hits in 71 CRISPR screens.
DR ChiTaRS; Eif4ebp2; mouse.
DR PRO; PR:P70445; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; P70445; protein.
DR Bgee; ENSMUSG00000020091; Expressed in extensor digitorum longus and 260 other tissues.
DR ExpressionAtlas; P70445; baseline and differential.
DR Genevisible; P70445; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0098794; C:postsynapse; ISO:MGI.
DR GO; GO:0008190; F:eukaryotic initiation factor 4E binding; IMP:UniProtKB.
DR GO; GO:0030371; F:translation repressor activity; IMP:UniProtKB.
DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:MGI.
DR GO; GO:0007613; P:memory; IMP:UniProtKB.
DR GO; GO:0050804; P:modulation of chemical synaptic transmission; IDA:UniProtKB.
DR GO; GO:0045947; P:negative regulation of translational initiation; IMP:UniProtKB.
DR GO; GO:0048167; P:regulation of synaptic plasticity; IMP:UniProtKB.
DR GO; GO:0006446; P:regulation of translational initiation; TAS:MGI.
DR GO; GO:0035176; P:social behavior; IMP:UniProtKB.
DR GO; GO:0031929; P:TOR signaling; IDA:MGI.
DR InterPro; IPR008606; EIF4EBP.
DR Pfam; PF05456; eIF_4EBP; 1.
PE 1: Evidence at protein level;
KW Phosphoprotein; Protein synthesis inhibitor; Reference proteome;
KW Translation regulation.
FT CHAIN 1..120
FT /note="Eukaryotic translation initiation factor 4E-binding
FT protein 2"
FT /id="PRO_0000190517"
FT MOTIF 54..60
FT /note="YXXXXLphi motif"
FT /evidence="ECO:0000250|UniProtKB:Q13542"
FT MOTIF 116..120
FT /note="TOS motif"
FT /evidence="ECO:0000269|PubMed:20347422"
FT MOD_RES 37
FT /note="Phosphothreonine; by MTOR"
FT /evidence="ECO:0000269|PubMed:20347422,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 46
FT /note="Phosphothreonine; by MTOR"
FT /evidence="ECO:0000269|PubMed:20347422,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 65
FT /note="Phosphoserine; by MTOR"
FT /evidence="ECO:0000269|PubMed:20347422,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 70
FT /note="Phosphothreonine; by MTOR"
FT /evidence="ECO:0000269|PubMed:20347422,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 83
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13542"
FT MOD_RES 99
FT /note="Deamidated asparagine"
FT /evidence="ECO:0000269|PubMed:20347422,
FT ECO:0000269|PubMed:20424163"
FT MOD_RES 102
FT /note="Deamidated asparagine"
FT /evidence="ECO:0000269|PubMed:20347422,
FT ECO:0000269|PubMed:20424163"
FT MUTAGEN 37
FT /note="T->A: Impaired hyperphosphorylation."
FT /evidence="ECO:0000269|PubMed:20347422"
FT MUTAGEN 46
FT /note="T->A: Impaired hyperphosphorylation."
FT /evidence="ECO:0000269|PubMed:20347422"
FT MUTAGEN 70
FT /note="T->A: Does not greatlay affect
FT hyperphosphorylation."
FT /evidence="ECO:0000269|PubMed:20347422"
FT MUTAGEN 99..102
FT /note="NNLN->ANLA: Abolishes deamidation and impaired
FT interaction with RPTOR."
FT /evidence="ECO:0000269|PubMed:20347422"
FT MUTAGEN 99..102
FT /note="NNLN->DNLD: Increased interaction with RPTOR."
FT /evidence="ECO:0000269|PubMed:20347422"
FT MUTAGEN 116..120
FT /note="Missing: Abolishes interaction with RPTOR."
FT /evidence="ECO:0000269|PubMed:20347422"
SQ SEQUENCE 120 AA; 12898 MW; 0A1ACC082583F769 CRC64;
MSASAGGSHQ PSQSRAIPTR TVAISDAAQL PQDYCTTPGG TLFSTTPGGT RIIYDRKFLL
DRRNSPMAQT PPCHLPNIPG VTSPGALIED SKVEVNNLNN LNNHDRKHAV GDEAQFEMDI
