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Q06507 (ATF4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 108. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cyclic AMP-dependent transcription factor ATF-4

Short name=cAMP-dependent transcription factor ATF-4
Alternative name(s):
Activating transcription factor 4
C/EBP-related ATF
Short name=C/ATF
Tax-responsive enhancer element-binding protein 67 homolog
Short name=TaxREB67 homolog
Gene names
Name:Atf4
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length349 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Transcriptional activator. Binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Binds to asymmetric CRE's as a heterodimer and to palindromic CRE's as a homodimer. Cooperates with FOXO1 in osteoblasts to regulate glucose homeostasis through suppression of beta-cell production and decrease in insulin production. Regulates the induction of DDIT3/CHOP and asparagine synthetase (ASNS) in response to ER stress. In concert with DDIT3/CHOP, activates the transcription of TRIB3 and promotes ER stress-induced neuronal apoptosis by regulating the transcriptional induction of BBC3/PUMA. Activates transcription of SIRT4. Ref.1 Ref.6 Ref.10 Ref.11 Ref.12

Subunit structure

Binds DNA as a homo- or heterodimer. Interacts with CEP290 (via an N-terminal region). Interacts with NEK6, DAPK2 (isoform 2)and ZIPK/DAPK3. Interacts (via its leucine zipper domain) with GABBR1 and GABBR2 (via their C-termini) By similarity. Forms a heterodimer with TXLNG in osteoblasts. Interacts (via its DNA binding domain) with FOXO1 (C-terminal half); the interaction occurs in osteoblasts and regulates glucose homeostasis through suppression of beta-cell proliferation and a decrease in insulin production. Interacts with SATB2; the interaction results in enhanced DNA binding and transactivation by these transcription factors. Interacts with DDIT3/CHOP By similarity. Ref.1 Ref.7 Ref.8 Ref.11

Subcellular location

Cytoplasm. Cell membrane. Nucleus. Cytoplasmcytoskeletonmicrotubule organizing centercentrosome By similarity. Note: Colocalizes with GABBR1 in hippocampal neuron dendritic membranes. Colocalizes with NEK6 in the centrosome By similarity. Ref.1 Ref.9 Ref.11

Developmental stage

At E16.5, expressed in osteoblasts surrounding newly formed trabecular bone. At postnatal day 2, detected in most osteoblasts and lining cells. By postnatal week 4, is detected in fewer osteoblasts, but remains present in lining cells (at protein level). Ref.9

Induction

By ER stress. Ref.10

Domain

The BetaTrCP degron motif promotes binding to BTRC when phosphorylated (Ref.12).

Post-translational modification

Ubiquitinated by SCF(BTRC) in response to mTORC1 signal, followed by proteasomal degradation and leading to down-regulate expression of SIRT4. Ref.12

Phosphorylated by NEK6 By similarity. Phosphorylated on the betaTrCP degron motif at Ser-218, followed by phosphorylation at Thr-212, Ser-223, Ser-230, Ser-234 and Ser-247, promoting interaction with BTRC and ubiquitination. Phosphorylation is promoted by mTORC1. Ref.12

Disruption phenotype

Null mice exhibit an increase in serum insulin levels and low blood glucose levels. There is a decrease in total fat content, gonadal fat, lean mass and body weight. Serum levels of osteocalcin/BGLAP are decreased. PBK/AKT1-mediated phosphorylation of FOXO1 at 'Ser-258' is increased with a subsequent decrease of FOXO1-mediated transcriptional activity. Ref.11

Sequence similarities

Belongs to the bZIP family.

Contains 1 bZIP (basic-leucine zipper) domain.

Sequence caution

The sequence AAA53043.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
   Cellular componentCell membrane
Cytoplasm
Cytoskeleton
Membrane
Nucleus
   LigandDNA-binding
   Molecular functionActivator
   PTMPhosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processgamma-aminobutyric acid signaling pathway

Inferred from electronic annotation. Source: Ensembl

gluconeogenesis

Inferred from direct assay PubMed 11916968. Source: MGI

intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress

Inferred from mutant phenotype Ref.10. Source: UniProtKB

negative regulation of potassium ion transport

Inferred from electronic annotation. Source: Ensembl

positive regulation of neuron apoptotic process

Inferred from mutant phenotype Ref.10. Source: UniProtKB

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay Ref.12. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 12749859. Source: MGI

regulation of transcription, DNA-templated

Inferred from mutant phenotype Ref.6Ref.10. Source: UniProtKB

response to endoplasmic reticulum stress

Inferred from direct assay Ref.10. Source: UniProtKB

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentcytoplasm

Inferred from direct assay Ref.9. Source: UniProtKB

dendrite membrane

Inferred from electronic annotation. Source: Ensembl

microtubule organizing center

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from direct assay Ref.9. Source: UniProtKB

transcription factor complex

Inferred from direct assay Ref.8. Source: MGI

   Molecular_functionDNA binding

Inferred from direct assay PubMed 12749859PubMed 15724149. Source: MGI

protein binding

Inferred from physical interaction PubMed 12749859PubMed 1371974Ref.7. Source: UniProtKB

sequence-specific DNA binding

Inferred from electronic annotation. Source: InterPro

sequence-specific DNA binding transcription factor activity

Inferred from direct assay Ref.12. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Trib3Q8K4K23EBI-77383,EBI-448962

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 349349Cyclic AMP-dependent transcription factor ATF-4
PRO_0000076585

Regions

Domain276 – 33964bZIP
Region278 – 29821Basic motif By similarity
Region303 – 33937Interaction with GABBR1 By similarity
Region304 – 33229Leucine-zipper By similarity
Motif214 – 22310BetaTrCP degron motif

Amino acid modifications

Modified residue2121Phosphothreonine Ref.12
Modified residue2181Phosphoserine Ref.12
Modified residue2231Phosphoserine Ref.12
Modified residue2301Phosphoserine Ref.12
Modified residue2341Phosphoserine Ref.12
Modified residue2471Phosphoserine Ref.12

Experimental info

Mutagenesis2121T → A: Promotes stabilization due to impaired ubiquitination; when associated with A-223; A-230; A-234 and A-247. Ref.12
Mutagenesis2181S → A: Promotes stabilization due to impaired ubiquitination. Ref.12
Mutagenesis2231S → A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-230; A-234 and A-247. Ref.12
Mutagenesis2301S → A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-223; A-234 and A-247. Ref.12
Mutagenesis2341S → A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-223; A-230 and A-247. Ref.12
Mutagenesis2471S → A: Promotes stabilization due to impaired ubiquitination; when associated with A-212; A-223; A-230 and A-234. Ref.12
Sequence conflict3451K → Q in AAA40476. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Q06507 [UniParc].

Last modified July 27, 2011. Version 2.
Checksum: 0C3F895755B1C7B9

FASTA34938,355
        10         20         30         40         50         60 
MTEMSFLNSE VLAGDLMSPF DQSGLGAEES LGLLDDYLEV AKHLKPHGFS SDKAGSSEWP 

        70         80         90        100        110        120 
AMDDGLASAS DTGKEDAFSG TDWMLEKMDL KEFDFDALFR MDDLETMPDE LLTTLDDTCD 

       130        140        150        160        170        180 
LFAPLVQETN KEPPQTVNPI GHLPESLIKV DQVAPFTFLQ PFPCSPGVLS STPEHSFSLE 

       190        200        210        220        230        240 
LGSEVDISEG DRKPDSAAYI TLIPPCVKEE DTPSDNDSGI CMSPESYLGS PQHSPSTSRA 

       250        260        270        280        290        300 
PPDNLPSPGG SRGSPRPKPY DPPGVSLTAK VKTEKLDKKL KKMEQNKTAA TRYRQKKRAE 

       310        320        330        340 
QEALTGECKE LEKKNEALKE KADSLAKEIQ YLKDLIEEVR KARGKKRVP 

« Hide

References

« Hide 'large scale' references
[1]"C/ATF, a member of the activating transcription factor family of DNA-binding proteins, dimerizes with CAAT/enhancer-binding proteins and directs their binding to cAMP response elements."
Vallejo M., Ron D., Miller C.P., Habener J.F.
Proc. Natl. Acad. Sci. U.S.A. 90:4679-4683(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBUNIT, SUBCELLULAR LOCATION.
Tissue: Adipocyte.
[2]"Protein interaction cloning in yeast: identification of mammalian proteins that react with the leucine zipper of Jun."
Chevray P.M., Nathans D.
Proc. Natl. Acad. Sci. U.S.A. 89:5789-5793(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: CD-1.
Tissue: Embryo.
[3]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: BALB/c, C57BL/6J and NOD.
Tissue: Lung, Spinal cord and Spleen.
[4]Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6.
Tissue: Eye.
[6]"TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death."
Ohoka N., Yoshii S., Hattori T., Onozaki K., Hayashi H.
EMBO J. 24:1243-1255(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[7]"FIAT represses ATF4-mediated transcription to regulate bone mass in transgenic mice."
Yu V.W., Ambartsoumian G., Verlinden L., Moir J.M., Prud'homme J., Gauthier C., Roughley P.J., St-Arnaud R.
J. Cell Biol. 169:591-601(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TXLNG.
[8]"SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation."
Dobreva G., Chahrour M., Dautzenberg M., Chirivella L., Kanzler B., Farinas I., Karsenty G., Grosschedl R.
Cell 125:971-986(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SATB2.
[9]"FIAT is co-expressed with its dimerization target ATF4 in early osteoblasts, but not in osteocytes."
Yu V.W., Akhouayri O., St-Arnaud R.
Gene Expr. Patterns 9:335-340(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: DEVELOPMENTAL STAGE, SUBCELLULAR LOCATION.
[10]"Neuronal apoptosis induced by endoplasmic reticulum stress is regulated by ATF4-CHOP-mediated induction of the Bcl-2 homology 3-only member PUMA."
Galehdar Z., Swan P., Fuerth B., Callaghan S.M., Park D.S., Cregan S.P.
J. Neurosci. 30:16938-16948(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION.
[11]"FoxO1 protein cooperates with ATF4 protein in osteoblasts to control glucose homeostasis."
Kode A., Mosialou I., Silva B.C., Joshi S., Ferron M., Rached M.T., Kousteni S.
J. Biol. Chem. 287:8757-8768(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, INTERACTION WITH FOXO1, FUNCTION.
[12]"The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4."
Csibi A., Fendt S.M., Li C., Poulogiannis G., Choo A.Y., Chapski D.J., Jeong S.M., Dempsey J.M., Parkhitko A., Morrison T., Henske E.P., Haigis M.C., Cantley L.C., Stephanopoulos G., Yu J., Blenis J.
Cell 153:840-854(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, UBIQUITINATION, PHOSPHORYLATION AT THR-212; SER-218; SER-223; SER-230; SER-234 AND SER-247, MUTAGENESIS OF THR-212; SER-218; SER-223; SER-230; SER-234 AND SER-247.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L13791 mRNA. Translation: AAA40476.1.
M94087 mRNA. Translation: AAA53043.1. Different initiation.
AK138657 mRNA. Translation: BAE23736.1.
AK144777 mRNA. Translation: BAE26060.1.
AK146193 mRNA. Translation: BAE26967.1.
AK156298 mRNA. Translation: BAE33662.1.
CH466550 Genomic DNA. Translation: EDL04604.1.
CH466550 Genomic DNA. Translation: EDL04605.1.
BC085169 mRNA. Translation: AAH85169.1.
CCDSCCDS37145.1.
RefSeqNP_001274109.1. NM_001287180.1.
NP_033846.2. NM_009716.3.
UniGeneMm.641.

3D structure databases

ProteinModelPortalQ06507.
SMRQ06507. Positions 284-339.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid198235. 12 interactions.
DIPDIP-30969N.
IntActQ06507. 2 interactions.

PTM databases

PhosphoSiteQ06507.

Proteomic databases

PRIDEQ06507.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000109605; ENSMUSP00000105234; ENSMUSG00000042406.
GeneID11911.
KEGGmmu:11911.
UCSCuc007wvl.1. mouse.

Organism-specific databases

CTD468.
MGIMGI:88096. Atf4.

Phylogenomic databases

eggNOGNOG325856.
GeneTreeENSGT00530000063801.
HOVERGENHBG004301.
KOK04374.
OMAGECRELE.
OrthoDBEOG72JWGW.
TreeFamTF316136.

Gene expression databases

ArrayExpressQ06507.
BgeeQ06507.
CleanExMM_ATF4.
GenevestigatorQ06507.

Family and domain databases

InterProIPR004827. bZIP.
[Graphical view]
PfamPF00170. bZIP_1. 1 hit.
[Graphical view]
SMARTSM00338. BRLZ. 1 hit.
[Graphical view]
PROSITEPS50217. BZIP. 1 hit.
PS00036. BZIP_BASIC. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSATF4. mouse.
NextBio279981.
PROQ06507.
SOURCESearch...

Entry information

Entry nameATF4_MOUSE
AccessionPrimary (citable) accession number: Q06507
Secondary accession number(s): Q5U4B2, Q61906
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: July 27, 2011
Last modified: July 9, 2014
This is version 108 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot