P12841 (FOS_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Proto-oncogene c-Fos

Alternative name(s):
Cellular oncogene fos

Gene names

Name:

Fos

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	380 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Nuclear phosphoprotein which forms a tight but non-covalently linked complex with the JUN/AP-1 transcription factor. On TGF-beta activation, forms a multimeric SMAD3/SMAD4/JUN/FOS complex, at the AP1/SMAD-binding site to regulate TGF-beta-mediated signaling By similarity. Has a critical function in regulating the development of cells destined to form and maintain the skeleton. It is thought to have an important role in signal transduction, cell proliferation and differentiation. In growing cells, activates phospholipid synthesis, possibly by activating CDS1 and PI4K2A. This activity requires Tyr-dephosphorylation and association with the endoplasmic reticulum By similarity. Ref.5 Ref.6
Subunit structure	Heterodimer; with JUN By similarity. Component of the SMAD3/SMAD4/JUN/FOS complex required for syngernistic TGF-beta-mediated transcription at the AP1 promoter site. Interacts with SMAD3; the interaction is weak even on TGF-beta activation. Interacts with DSIPI; this interaction inhibits the binding of active AP1 to its target DNA By similarity. Interacts with MAFB. Interacts with CDS1 and PI4K2A By similarity. Ref.4
Subcellular location	Nucleus By similarity. Endoplasmic reticulum By similarity. Cytoplasm › cytosol By similarity. Note: In quiescent cells, present in very small amounts in the cytosol. Following induction of cell growth, first localizes to the endoplasmic reticulum and only later to the nucleus. Localization at the endoplasmic reticulum requires dephosphorylation at Tyr-10 and Tyr-30 By similarity.
Post-translational modification	Phosphorylated in the C-terminal upon stimulation by nerve growth factor (NGF) and epidermal growth factor (EGF) By similarity. Phosphorylated, in vitro, by MAPK and RSK1. Phosphorylation on both Ser-362 and Ser-374 by MAPK1/2 and RSK1/2 leads to protein stabilization with phosphorylation on Ser-374 being the major site for protein stabilization on NGF stimulation. Phosphorylation on Ser-362 and Ser-374 primes further phosphorylations on Thr-325 and Thr-331 through promoting docking of MAPK to the DEF domain. Phosphorylation on Thr-232, induced by HA-RAS, activates the transcriptional activity and antagonizes sumoylation. Phosphorylation on Ser-362 by RSK2 in osteoblasts contributes to osteoblast transformation. Ref.5 Ref.6 Constitutively sumoylated with SUMO1, SUMO2 and SUMO3. Desumoylated by SENP2. Sumoylation requires heterodimerization with JUN and is enhanced by mitogen stimulation. Sumoylation inhibits the AP-1 transcriptional activity and is, itself, inhibited by Ras-activated phosphorylation on Thr-232 By similarity. In quiescent cells, the small amount of FOS present is phosphorylated at Tyr-10 and Tyr-30 by SRC. This Tyr-phosphorylated form is cytosolic. In growing cells, dephosphorylated by PTPN2. Dephosphorylation leads to the association with endoplasmic reticulum membranes and activation of phospholipid synthesis By similarity. Ref.5 Ref.6
Sequence similarities	Belongs to the bZIP family. Fos subfamily. Contains 1 bZIP (basic-leucine zipper) domain.

Ontologies

Keywords
Cellular component	Cytoplasm Endoplasmic reticulum Nucleus
Disease	Proto-oncogene
Ligand	DNA-binding
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	SMAD protein signal transduction Inferred from electronic annotation. Source: Compara aging Inferred from expression pattern PubMed 11389931. Source: RGD cellular response to calcium ion Inferred from electronic annotation. Source: Compara cellular response to extracellular stimulus Inferred from electronic annotation. Source: Compara cellular response to hormone stimulus Inferred from expression pattern PubMed 11460264. Source: RGD cellular response to reactive oxygen species Inferred from electronic annotation. Source: Compara conditioned taste aversion Inferred from expression pattern PubMed 18374904. Source: RGD female pregnancy Inferred from expression pattern PubMed 12080023. Source: RGD nervous system development Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara response to cAMP Inferred from expression pattern PubMed 18280640. Source: RGD response to cold Inferred from expression pattern PubMed 16169632. Source: RGD response to corticosterone stimulus Inferred from expression pattern PubMed 18485334. Source: RGD response to cytokine stimulus Inferred from expression pattern PubMed 18280640. Source: RGD response to drug Inferred from expression pattern PubMed 12243769. Source: RGD response to gravity Inferred from expression pattern PubMed 17274184. Source: RGD response to light stimulus Inferred from expression pattern PubMed 11146118. Source: RGD response to lipopolysaccharide Inferred from expression pattern PubMed 11389931. Source: RGD response to mechanical stimulus Inferred from expression pattern PubMed 15126239. Source: RGD response to progesterone stimulus Inferred from expression pattern PubMed 12080023. Source: RGD response to toxic substance Inferred from expression pattern PubMed 11295234. Source: RGD sleep Inferred from expression pattern PubMed 17274184. Source: RGD transcription from RNA polymerase II promoter Inferred from mutant phenotype PubMed 10830307. Source: RGD transforming growth factor beta receptor signaling pathway Inferred from electronic annotation. Source: Compara
Cellular_component	membrane Inferred from direct assay PubMed 10891591. Source: RGD neuron projection Inferred from direct assay PubMed 10891591. Source: RGD nucleus Inferred from direct assay PubMed 19033670PubMed 7595148. Source: MGI transcription factor complex Inferred from electronic annotation. Source: Compara
Molecular_function	double-stranded DNA binding Inferred from direct assay PubMed 10830307Ref.3. Source: RGD protein heterodimerization activity Inferred from direct assay Ref.3. Source: RGD sequence-specific DNA binding Inferred from direct assay PubMed 10830307. Source: RGD sequence-specific DNA binding transcription factor activity Inferred from mutant phenotype PubMed 10830307. Source: RGD transcription regulatory region DNA binding Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 380	380	Proto-oncogene c-Fos		PRO_0000076469
Regions
	Domain	137 – 200	64	bZIP
	Region	139 – 159	21	Basic motif; required for the activation of phospholipid synthesis, but not for CDS1-binding By similarity
	Region	165 – 193	29	Leucine-zipper By similarity
Amino acid modifications
	Modified residue	10	1	Phosphotyrosine; by SRC By similarity
	Modified residue	30	1	Phosphotyrosine; by SRC By similarity
	Modified residue	232	1	Phosphothreonine Ref.5
	Modified residue	325	1	Phosphothreonine; by MAPK1 and MAPK3 Ref.6
	Modified residue	331	1	Phosphothreonine; by MAPK1 and MAPK3 Ref.6
	Modified residue	362	1	Phosphoserine; by MAPK1, MAPK3 and RPS6KA3 Ref.6
	Modified residue	374	1	Phosphoserine; by MAPK1 and MAPK3 Ref.6
	Cross-link	113		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
	Cross-link	265		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity
Experimental info
	Mutagenesis	232	1	T → A: Abolishes HA-RAS-mediated activation. Loss of in vitro ERK2-mediated phosphorylation. No change in sumoylation levels. Ref.5
	Mutagenesis	325	1	T → A: Loss of NGF-mediated phosphorylation; when associated with A-331. Ref.6
	Mutagenesis	331	1	T → A: Loss of NGF-mediated phosphorylation; when associated with A-325. Ref.6
	Mutagenesis	343 – 345	3	FTY → ATA: Decreased phosphorylation levels. Reduced NGF-mediated enhanced transactivation. Ref.6
	Mutagenesis	362	1	S → A: Some loss of protein stabilization on NGF-treatment; when associated with D-374. Ref.6
	Mutagenesis	362	1	S → D: Increased protein stabilization on NGF-treatment, but no increase when treated with MAPK-inhibitor; when associated with D-374. Ref.6
	Mutagenesis	374	1	S → A: Greatly reduced protein stabilization on NGF stimulation. Ref.6
	Mutagenesis	374	1	S → D: Increased protein stabilization on NGF-treatment, but no increase when treated with MAPK-inhibitor; when associated with D-362. Some loss of protein stablization on NGF-treatment; wnen associated with A-362. Ref.6

Sequences

	Sequence		Length	Mass (Da)
	P12841 [UniParc]. Last modified October 1, 1989. Version 1. Checksum: E62D16A88CB2BEE9	FASTA	380	40,927
	10 20 30 40 50 60 MMFSGFNADY EASSSRCSSA SPAGDSLSYY HSPADSFSSM GSPVNTQDFC ADLSVSSANF 70 80 90 100 110 120 IPTVTAISTS PDLQWLVQPT LVSSVAPSQT RAPHPYGLPT PSTGAYARAG VVKTMSGGRA 130 140 150 160 170 180 QSIGRRGKVE QLSPEEEEKR RIRRERNKMA AAKCRNRRRE LTDTLQAETD QLEDEKSALQ 190 200 210 220 230 240 TEIANLLKEK EKLEFILAAH RPACKIPNDL GFPEEMSVTS LDLTGGLPEA TTPESEEAFT 250 260 270 280 290 300 LPLLNDPEPK PSLEPVKNIS NMELKAEPFD DFLFPASSRP SGSETARSVP DVDLSGSFYA 310 320 330 340 350 360 ADWEPLHSSS LGMGPMVTEL EPLCTPVVTC TPSCTTYTSS FVFTYPEADS FPSCAAAHRK 370 380 GSSSNEPSSD SLSSPTLLAL

References

[1]	"Isolation and characterization of the c-fos(rat) cDNA and analysis of post-translational modification in vitro." Curran T., Gordon M.B., Rubino K.L., Sambucetti L.C. Oncogene 2:79-84(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"cFOS expression in rat." Weiler E. Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: Sprague-Dawley. Tissue: Liver.
[3]	"Expression and purification of the leucine zipper and DNA-binding domains of Fos and Jun: both Fos and Jun contact DNA directly." Abate C., Luk D., Gentz R., Rauscher F.J. III, Curran T. Proc. Natl. Acad. Sci. U.S.A. 87:1032-1036(1990) [PubMed] [Europe PMC] [Abstract] Cited for: DNA-BINDING.
[4]	"Rat maf-related factors: the specificities of DNA binding and heterodimer formation." Matsushima-Hibiya Y., Nishi S., Sakai M. Biochem. Biophys. Res. Commun. 245:412-418(1998) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MAFB.
[5]	"Phosphorylation of the c-Fos and c-Jun HOB1 motif stimulates its activation capacity." Bannister A.J., Brown H.J., Sutherland J.A., Kouzarides T. Nucleic Acids Res. 22:5173-5176(1994) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-232, FUNCTION, MUTAGENESIS OF THR-232.
[6]	"Sustained activation of extracellular signal-regulated kinase by nerve growth factor regulates c-fos protein stabilization and transactivation in PC12 cells." Pellegrino M.J., Stork P.J. J. Neurochem. 99:1480-1493(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT THR-325; THR-331; SER-362 AND SER-374, FUNCTION, MUTAGENESIS OF THR-325; THR-331; 343-PHE--TYR-345; SER-362 AND SER-374.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X06769 mRNA. Translation: CAA29937.1. DQ089699 Genomic DNA. Translation: AAZ13764.1.
IPI	IPI00368000.
PIR	TVRTFS. A28263.
RefSeq	NP_071533.1. NM_022197.2.
UniGene	Rn.103750.
3D structure databases
ProteinModelPortal	P12841.
SMR	P12841. Positions 140-192.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-6001N.
MINT	MINT-220035.
PTM databases
PhosphoSite	P12841.
Proteomic databases
PaxDb	P12841.
PRIDE	P12841.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000010712; ENSRNOP00000010712; ENSRNOG00000008015.
GeneID	314322.
KEGG	rno:314322.
UCSC	RGD:2626. rat.
Organism-specific databases
CTD	2353. 2557.
RGD	2626. Fos.
Phylogenomic databases
eggNOG	NOG258795.
GeneTree	ENSGT00550000074426.
HOGENOM	HOG000234334.
HOVERGEN	HBG005743.
InParanoid	P12841.
KO	K04379.
OMA	YYPSPAG.
OrthoDB	EOG42BX9D.
Gene expression databases
ArrayExpress	P12841.
Genevestigator	P12841.
GermOnline	ENSRNOG00000008015. Rattus norvegicus.
Family and domain databases
InterPro	IPR004827. bZIP. IPR000837. Leuzip_Fos. [Graphical view]
Pfam	PF00170. bZIP_1. 1 hit. [Graphical view]
PRINTS	PR00042. LEUZIPPRFOS.
SMART	SM00338. BRLZ. 1 hit. [Graphical view]
PROSITE	PS50217. BZIP. 1 hit. PS00036. BZIP_BASIC. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	620671.

Entry information

Entry name

FOS_RAT

Accession

Primary (citable) accession number: P12841
Secondary accession number(s): Q4FDN1

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1989
Last sequence update:	October 1, 1989
Last modified:	May 29, 2013
This is version 113 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program