P01100 (FOS_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Proto-oncogene c-Fos

Alternative name(s):
Cellular oncogene fos
G0/G1 switch regulatory protein 7

Gene names

Name:	FOS
Synonyms:	G0S7

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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. In the heterodimer, FOS and JUN/AP-1 basic regions each seems to interact with symmetrical DNA half sites. On TGF-beta activation, forms a multimeric SMAD3/SMAD4/JUN/FOS complex at the AP1/SMAD-binding site to regulate TGF-beta-mediated signaling. 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. Ref.9 Ref.10 Ref.12
Subunit structure	Heterodimer; with JUN By similarity. Interacts with MAFB 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 MAFB. Interacts with DSIPI; this interaction inhibits the binding of active AP1 to its target DNA. Ref.6 Ref.10
Subcellular location	Nucleus Ref.12.
Post-translational modification	Phosphorylated in the C-terminal upon stimulation by nerve growth factor (NGF) and epidermal growth factor (EGF). 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 By similarity. Ref.9 Ref.11 Constitutively sumoylated by 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. Ref.12 Ref.14
Sequence similarities	Belongs to the bZIP family. Fos subfamily. Contains 1 bZIP domain.

Ontologies

Keywords
Cellular component	Nucleus
Disease	Proto-oncogene
Ligand	DNA-binding
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	DNA methylation Traceable author statement. Source: ProtInc MyD88-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome MyD88-independent toll-like receptor signaling pathway Traceable author statement. Source: Reactome SMAD protein signal transduction Inferred from direct assay Ref.10. Source: BHF-UCL Toll signaling pathway Traceable author statement. Source: Reactome cellular response to reactive oxygen species Inferred from direct assay. Source: BHF-UCL inflammatory response Traceable author statement. Source: ProtInc innate immune response Traceable author statement. Source: Reactome regulation of sequence-specific DNA binding transcription factor activity Traceable author statement. Source: Reactome stress-activated MAPK cascade Traceable author statement. Source: Reactome toll-like receptor 1 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 3 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome transcription from RNA polymerase II promoter Traceable author statement. Source: ProtInc transforming growth factor beta receptor signaling pathway Inferred from direct assay Ref.10. Source: BHF-UCL
Molecular function	R-SMAD binding Inferred from physical interaction Ref.10. Source: BHF-UCL protein dimerization activity Inferred from electronic annotation. Source: InterPro sequence-specific DNA binding transcription factor activity Inferred from direct assay Ref.10. Source: BHF-UCL transcription regulatory region DNA binding Inferred from direct assay Ref.10. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
APP	P05067	3	EBI-852851,EBI-77613
ATF2	P15336	4	EBI-852851,EBI-1170906
CLU	P10909	2	EBI-852851,EBI-1104674
COPS4	Q9BT78	2	EBI-852851,EBI-742413
JUN	P05412	6	EBI-852851,EBI-852823
JUND	P17535	3	EBI-852851,EBI-2682803
ZNF133	P52736	4	EBI-852851,EBI-2687350

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 380

380

Proto-oncogene c-Fos

PRO_0000076465

Regions

Domain

165 – 193

29

Leucine-zipper

DNA binding

139 – 160

22

Basic motif Ref.6 Ref.8

Amino acid modifications

Modified residue

232

1

Phosphothreonine By similarity

Modified residue

325

1

Phosphothreonine; by MAPK1 and MAPK3 Ref.11

Modified residue

331

1

Phosphothreonine; by MAPK1 and MAPK3 Ref.11

Modified residue

362

1

Phosphoserine; by MAPK1, MAPK3 and RPS6KA3 Ref.9

Modified residue

374

1

Phosphoserine; by MAPK1 and MAPK3 Ref.9 Ref.11

Cross-link

113

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Ref.13

Cross-link

265

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity

Experimental info

Mutagenesis

128

1

K → R: No change in sumoylation. Ref.12

Mutagenesis

192

1

K → R: No change in sumoylation. Ref.12

Mutagenesis

232

1

T → D: Decreased sumoylation levels.

Mutagenesis

265

1

K → R: Abolishes sumoylation. No change in nuclear location nor on protein stability. Increased AP1 transactivation activity when heterodimerized with cJUN. Ref.12

Mutagenesis

325

1

T → D: No change in sumoylation levels. Ref.12

Mutagenesis

331

1

T → D: No change in sumoylation levels. Ref.12

Mutagenesis

362

1

S → A: Loss of protein stability. Reduced MOS/MAPK-mediated transforming ability; when associated with A-374. Ref.9 Ref.12

Mutagenesis

362

1

S → D: Increased protein stability. Increased MOS/MAPK-mediated transforming ability and no change in sumoylation levels; when associated with D-374. Ref.9 Ref.12

Mutagenesis

374

1

S → A: No change in sumoylation levels. Loss of protein stability. Reduced MOS/MAPK-mediated transforming ability; when associated with A-362. Ref.9 Ref.12

Mutagenesis

374

1

S → D: Increased protein stability. Increased MOS/MAPK-mediated transforming ability and no change in sumoylation levels; when associated with D-362. Ref.9 Ref.12

Sequence conflict

133 – 144

12

SPEEE…RRIRR → ISRRRREKENPK no nucleotide entry Ref.6

Secondary structure

1

.

.

.

.

.

380

Helix Strand Turn

Details...

Helix

141 – 191

51

Helix

193 – 197

5

Sequences

	Sequence		Length	Mass (Da)
	P01100 [UniParc]. Last modified July 21, 1986. Version 1. Checksum: 9E3B2969347C90C8	FASTA	380	40,695
	10 20 30 40 50 60 MMFSGFNADY EASSSRCSSA SPAGDSLSYY HSPADSFSSM GSPVNAQDFC TDLAVSSANF 70 80 90 100 110 120 IPTVTAISTS PDLQWLVQPA LVSSVAPSQT RAPHPFGVPA PSAGAYSRAG VVKTMTGGRA 130 140 150 160 170 180 QSIGRRGKVE QLSPEEEEKR RIRRERNKMA AAKCRNRRRE LTDTLQAETD QLEDEKSALQ 190 200 210 220 230 240 TEIANLLKEK EKLEFILAAH RPACKIPDDL GFPEEMSVAS LDLTGGLPEV ATPESEEAFT 250 260 270 280 290 300 LPLLNDPEPK PSVEPVKSIS SMELKTEPFD DFLFPASSRP SGSETARSVP DMDLSGSFYA 310 320 330 340 350 360 ADWEPLHSGS LGMGPMATEL EPLCTPVVTC TPSCTAYTSS FVFTYPEADS FPSCAAAHRK 370 380 GSSSNEPSSD SLSSPTLLAL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Complete nucleotide sequence of a human c-onc gene: deduced amino acid sequence of the human c-fos protein." van Straaten F., Mueller R., Curran T., Van Beveren C., Verma I.M. Proc. Natl. Acad. Sci. U.S.A. 80:3183-3187(1983) [PubMed: 6574479] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	NIEHS SNPs program Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"The DNA sequence and analysis of human chromosome 14." Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., Du H. , Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., Waterston R., Hood L., Weissenbach J. Nature 421:601-607(2003) [PubMed: 12508121] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Pancreas.
[5]	"Retrovirus-mediated gene transfer of a human c-fos cDNA into mouse bone marrow stromal cells." Roux P., Verrier B., Klein B., Niccolino M., Marty L., Alexandre C., Piechaczyk M. Oncogene 6:2155-2160(1991) [PubMed: 1658710] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-6.
[6]	"Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers." Hai T., Liu F., Coukos W.J., Green M.R. Genes Dev. 3:2083-2090(1989) [PubMed: 2516827] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 133-200, DNA-BINDING, SUBUNIT.
[7]	Erratum Hai T., Liu F., Coukos W.J., Green M.R. Genes Dev. 4:682-682(1990)
[8]	"The basic region of Fos mediates specific DNA binding." Nakabeppu Y., Nathans D. EMBO J. 8:3833-3841(1989) [PubMed: 2511004] [Abstract] Cited for: DNA-BINDING.
[9]	"The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells." Okazaki K., Sagata N. EMBO J. 14:5048-5059(1995) [PubMed: 7588633] [Abstract] Cited for: PHOSPHORYLATION AT SER-362 AND SER-374, FUNCTION, MUTAGENESIS OF SER-362 AND SER-374.
[10]	"Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription." Zhang Y., Feng X.H., Derynck R. Nature 394:909-913(1998) [PubMed: 9732876] [Abstract] Cited for: IDENTIFICATION AS A COMPONENT OF THE SMAD3/SMAD4/JUN/FOS COMPLEX, FUNCTION, INTERACTION WITH SMAD3.
[11]	"Molecular interpretation of ERK signal duration by immediate early gene products." Murphy L.O., Smith S., Chen R.H., Fingar D.C., Blenis J. Nat. Cell Biol. 4:556-564(2002) [PubMed: 12134156] [Abstract] Cited for: PHOSPHORYLATION AT THR-325; THR-331 AND SER-374.
[12]	"Down-regulation of c-Fos/c-Jun AP-1 dimer activity by sumoylation." Bossis G., Malnou C.E., Farras R., Andermarcher E., Hipskind R., Rodriguez M., Schmidt D., Muller S., Jariel-Encontre I., Piechaczyk M. Mol. Cell. Biol. 25:6964-6979(2005) [PubMed: 16055710] [Abstract] Cited for: SUMOYLATION AT LYS-265, SUBCELLULAR LOCATION, FUNCTION, MUTAGENESIS OF LYS-128; LYS-192; LYS-265; THR-325; THR-331; SER-362 AND SER-374.
[13]	"The proteomic reactor facilitates the analysis of affinity-purified proteins by mass spectrometry: application for identifying ubiquitinated proteins in human cells." Vasilescu J., Zweitzig D.R., Denis N.J., Smith J.C., Ethier M., Haines D.S., Figeys D. J. Proteome Res. 6:298-305(2007) [PubMed: 17203973] [Abstract] Cited for: UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-113, MASS SPECTROMETRY. Tissue: Lung adenocarcinoma.
[14]	"Ubc9 fusion-directed SUMOylation identifies constitutive and inducible SUMOylation." Jakobs A., Himstedt F., Funk M., Korn B., Gaestel M., Niedenthal R. Nucleic Acids Res. 35:E109-E109(2007) [PubMed: 17709345] [Abstract] Cited for: SUMOYLATION.
[15]	"Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA." Glover J.N., Harrison S.C. Nature 373:257-261(1995) [PubMed: 7816143] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.05 ANGSTROMS) OF 139-198 OF COMPLEX WITH JUN.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

V01512 Genomic DNA. Translation: CAA24756.1.
K00650 Genomic DNA. Translation: AAA52471.1.
AY212879 Genomic DNA. Translation: AAO21129.1.
AF111167 Genomic DNA. Translation: AAC98315.1.
BC004490 mRNA. Translation: AAH04490.1.
S65138 mRNA. Translation: AAB20306.1.

IPI

IPI00033008.

PIR

TVHUF1. A01342.
E34223.

RefSeq

NP_005243.1. NM_005252.3.

UniGene

Hs.728789.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1A02	X-ray	2.70	F	139-193	[»]
1FOS	X-ray	3.05	E/G	139-200	[»]
1S9K	X-ray	3.10	D	140-192	[»]

ProteinModelPortal

P01100.

SMR

P01100. Positions 138-200.

DisProt

DP00078.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-1047N.

IntAct

P01100. 82 interactions.

MINT

MINT-105814.

STRING

P01100.

PTM databases

PhosphoSite

P01100.

Polymorphism databases

DMDM

120470.

Proteomic databases

PRIDE

P01100.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000303562; ENSP00000306245; ENSG00000170345.

GeneID

2353.

KEGG

hsa:2353.

UCSC

uc001xrn.1. human.

Organism-specific databases

CTD

2353.

GeneCards

GC14P075745.

H-InvDB

HIX0011826.

HGNC

HGNC:3796. FOS.

HPA

HPA018531.

MIM

164810. gene.

neXtProt

NX_P01100.

PharmGKB

PA28212.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG06597.

HOGENOM

HBG714812.

HOVERGEN

HBG005743.

InParanoid

P01100.

OMA

DWEPLHG.

OrthoDB

EOG42BX9D.

PhylomeDB

P01100.

Enzyme and pathway databases

Pathway_Interaction_DB

bcr_5pathway. BCR signaling pathway.
nfat_tfpathway. Calcineurin-regulated NFAT-dependent transcription in lymphocytes.
tcrcalciumpathway. Calcium signaling in the CD4+ TCR pathway.
cd8tcrdownstreampathway. Downstream signaling in naive CD8+ T cells.
endothelinpathway. Endothelins.
fcer1pathway. Fc-epsilon receptor I signaling in mast cells.
fgf_pathway. FGF signaling pathway.
hnf3apathway. FOXA1 transcription factor network.
foxm1pathway. FOXM1 transcription factor network.
hif1_tfpathway. HIF-1-alpha transcription factor network.
il12_stat4pathway. IL12 signaling mediated by STAT4.
il12_2pathway. IL12-mediated signaling events.
il2_1pathway. IL2-mediated signaling events.
il6_7pathway. IL6-mediated signaling events.
lysophospholipid_pathway. LPA receptor mediated events.
avb3_opn_pathway. Osteopontin-mediated events.
pdgfrapathway. PDGFR-alpha signaling pathway.
ps1pathway. Presenilin action in Notch and Wnt signaling.
tcrraspathway. Ras signaling in the CD4+ TCR pathway.
smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.
telomerasepathway. Regulation of Telomerase.
s1p_s1p2_pathway. S1P2 pathway.
met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met).
mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P01100.

Bgee

P01100.

CleanEx

HS_FOS.

Genevestigator

P01100.

GermOnline

ENSG00000170345. Homo sapiens.

Family and domain databases

InterPro

IPR004827. bZIP.
IPR011616. bZIP_1.
IPR000837. Leuzip_Fos.
[Graphical view]

KO

K04379.

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

9543.

SOURCE

Search...

Entry information

Entry name

FOS_HUMAN

Accession

Primary (citable) accession number: P01100
Secondary accession number(s): P18849

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 21, 1986
Last modified:	January 25, 2012
This is version 143 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.