P01100 (FOS_HUMAN) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 171. History...
Names and origin
|Protein names||Recommended name:|
Cellular oncogene fos
G0/G1 switch regulatory protein 7
|Organism||Homo sapiens (Human) [Reference proteome]|
|Taxonomic identifier||9606 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo|
|Sequence length||380 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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. In growing cells, activates phospholipid synthesis, possibly by activating CDS1 and PI4K2A. This activity requires Tyr-dephosphorylation and association with the endoplasmic reticulum. Ref.9 Ref.10 Ref.12 Ref.15 Ref.17
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. Interacts with CDS1 and PI4K2A By similarity. Ref.6 Ref.10
Nucleus. Endoplasmic reticulum. Cytoplasm › cytosol. 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. Ref.12 Ref.15 Ref.17
Expressed at very low levels in quiescent cells. When cells are stimulated to reenter growth, they undergo 2 waves of expression, the first one peaks 7.5 minutes following FBS induction. At this stage, the protein is localized endoplasmic reticulum. The second wave of expression occurs at about 20 minutes after induction and peaks at 1 hour. At this stage, the protein becomes nuclear. Ref.15
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 Ref.15 Ref.17
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. Ref.12 Ref.14
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. Ref.9 Ref.11 Ref.15 Ref.17
Contains 1 bZIP (basic-leucine zipper) domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 380||380||Proto-oncogene c-Fos||PRO_0000076465|
|Domain||137 – 200||64||bZIP|
|Region||139 – 159||21||Basic motif; required for the activation of phospholipid synthesis, but not for CDS1-binding|
|Region||165 – 193||29||Leucine-zipper By similarity|
Amino acid modifications
|Modified residue||10||1||Phosphotyrosine; by SRC Ref.15 Ref.17|
|Modified residue||30||1||Phosphotyrosine; by SRC Ref.15 Ref.17|
|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|
|Mutagenesis||10||1||Y → E: Loss of activation of phospholipid synthesis; when associated with E-30. Ref.15 Ref.17|
|Mutagenesis||10||1||Y → F: Overall loss of Tyr-phosphorylation, including that of Y-30 phosphorylation. Localizes to the endoplasmic reticulum in quiescent cells. Activates phospholipid synthesis in growing cells. Ref.15 Ref.17|
|Mutagenesis||30||1||Y → E: Loss of activation of phospholipid synthesis; when associated with E-10. Ref.15 Ref.17|
|Mutagenesis||30||1||Y → F: Overall loss of Tyr-phosphorylation, including that of Y-10 phosphorylation. Localizes to the endoplasmic reticulum in quiescent cells. Activates phospholipid synthesis in growing cells. Ref.15 Ref.17|
|Mutagenesis||106||1||Y → F: No effect on Tyr-phosphorylation. Loss of endoplasmic reticulum localization in quiescent cells. Ref.15|
|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||337||1||Y → F: No effect on Tyr-phosphorylation. Loss of endoplasmic reticulum localization in quiescent cells. Ref.15|
|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|
Helix Strand Turn
|Helix||141 – 191||51|
|||"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
|||NIEHS SNPs program|
Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
|||"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. Weissenbach J.
Nature 421:601-607(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"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].
|||"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-6.
|||"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 133-200, DNA-BINDING, SUBUNIT.
Hai T., Liu F., Coukos W.J., Green M.R.
Genes Dev. 4:682-682(1990)
|||"The basic region of Fos mediates specific DNA binding."|
Nakabeppu Y., Nathans D.
EMBO J. 8:3833-3841(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: DNA-BINDING.
|||"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] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-362 AND SER-374, FUNCTION, MUTAGENESIS OF SER-362 AND SER-374.
|||"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] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION AS A COMPONENT OF THE SMAD3/SMAD4/JUN/FOS COMPLEX, FUNCTION, INTERACTION WITH SMAD3.
|||"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] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-325; THR-331 AND SER-374.
|||"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] [Europe PMC] [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.
|||"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] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-113.
Tissue: Lung adenocarcinoma.
|||"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] [Europe PMC] [Abstract]
Cited for: SUMOYLATION.
|||"N-Terminal c-Fos tyrosine phosphorylation regulates c-Fos/ER association and c-Fos-dependent phospholipid synthesis activation."|
Portal M.M., Ferrero G.O., Caputto B.L.
Oncogene 26:3551-3558(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE, PHOSPHORYLATION AT TYR-10 AND TYR-30, MUTAGENESIS OF TYR-10; TYR-30; TYR-106 AND TYR-337.
|||"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."|
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
|||"The kinase c-Src and the phosphatase TC45 coordinately regulate c-Fos tyrosine phosphorylation and c-Fos phospholipid synthesis activation capacity."|
Ferrero G.O., Velazquez F.N., Caputto B.L.
Oncogene 31:3381-3391(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYR-10 AND TYR-30, MUTAGENESIS OF TYR-10 AND TYR-30.
|||"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] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.05 ANGSTROMS) OF 139-198 OF COMPLEX WITH JUN.
|+||Additional computationally mapped references.|
|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.
|PIR||TVHUF1. A01342. |
|RefSeq||NP_005243.1. NM_005252.3. |
3D structure databases
|SMR||P01100. Positions 138-200. |
Protein-protein interaction databases
|BioGrid||108636. 84 interactions.|
|IntAct||P01100. 86 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENST00000303562; ENSP00000306245; ENSG00000170345. |
|UCSC||uc001xrn.3. human. |
|HGNC||HGNC:3796. FOS. |
|MIM||164810. gene. |
|Orphanet||528. Berardinelli-Seip congenital lipodystrophy. |
Enzyme and pathway databases
|Reactome||REACT_120956. Cellular responses to stress. |
REACT_6782. TRAF6 Mediated Induction of proinflammatory cytokines.
REACT_6900. Immune System.
Gene expression databases
Family and domain databases
|InterPro||IPR004827. bZIP. |
|Pfam||PF00170. bZIP_1. 1 hit. |
|PRINTS||PR00042. LEUZIPPRFOS. |
|SMART||SM00338. BRLZ. 1 hit. |
|PROSITE||PS50217. BZIP. 1 hit. |
PS00036. BZIP_BASIC. 1 hit.
|ChiTaRS||Fos. human. |
|Accession||Primary (citable) accession number: P01100|
Secondary accession number(s): P18849
|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.|
Index of protein domains and families
Index of Protein Data Bank (PDB) cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
|Human chromosome 14|
Human chromosome 14: entries, gene names and cross-references to MIM