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Q99958 (FOXC2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 140. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Forkhead box protein C2
Alternative name(s):
Forkhead-related protein FKHL14
Mesenchyme fork head protein 1
Short name=MFH-1 protein
Transcription factor FKH-14
Gene names
Name:FOXC2
Synonyms:FKHL14, MFH1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length501 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Transcriptional activator. Might be involved in the formation of special mesenchymal tissues. Ref.1

Subcellular location

Nucleus Ref.13.

Post-translational modification

Phosphorylation regulates FOXC2 transcriptional activity by promoting its recruitment to chromatin.

Involvement in disease

Lymphedema, hereditary, 2 (LMPH2) [MIM:153200]: A chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections, and physical impairment.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.4

Lymphedema-yellow nails (LYYN) [MIM:153300]: A disorder characterized by yellow, dystrophic, thick and slowly growing nails, associated with lymphedema and respiratory involvement. Lymphedema occurs more often in the lower limbs. It can appear at birth or later in life. Onset generally follows the onset of ungual abnormalities.
Note: The disease is caused by mutations affecting the gene represented in this entry.

Lymphedema-distichiasis (LYD) [MIM:153400]: A disorder characterized by primary limb lymphedema usually starting at puberty (but in some cases later or at birth) and associated with distichiasis (double rows of eyelashes, with extra eyelashes growing from the Meibomian gland orifices). Drooping of the upper eyelid (ptosis) is a variable feature of the lymphedema-distichiasis syndrome, occurring in about 30% of patients.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.15

Sequence similarities

Contains 1 fork-head DNA-binding domain.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
   Cellular componentNucleus
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   LigandDNA-binding
   Molecular functionActivator
Developmental protein
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processNotch signaling pathway

Inferred from Biological aspect of Ancestor. Source: RefGenome

artery morphogenesis

Inferred from Biological aspect of Ancestor. Source: RefGenome

blood vessel remodeling

Inferred from Biological aspect of Ancestor. Source: RefGenome

camera-type eye development

Inferred from Biological aspect of Ancestor. Source: RefGenome

cardiac muscle cell proliferation

Inferred from Biological aspect of Ancestor. Source: RefGenome

collagen fibril organization

Inferred from Biological aspect of Ancestor. Source: RefGenome

embryonic heart tube development

Inferred from Biological aspect of Ancestor. Source: RefGenome

embryonic viscerocranium morphogenesis

Inferred from Biological aspect of Ancestor. Source: RefGenome

glomerular endothelium development

Inferred from electronic annotation. Source: Ensembl

glomerular mesangial cell development

Inferred from electronic annotation. Source: Ensembl

glomerular visceral epithelial cell differentiation

Inferred from electronic annotation. Source: Ensembl

heart development

Inferred from mutant phenotype PubMed 21457232. Source: DFLAT

insulin receptor signaling pathway

Inferred from direct assay PubMed 16456100. Source: UniProtKB

lymphangiogenesis

Inferred from mutant phenotype PubMed 12114478. Source: UniProtKB

mesoderm development

Non-traceable author statement PubMed 8674414. Source: UniProtKB

metanephros development

Inferred from Biological aspect of Ancestor. Source: RefGenome

negative regulation of apoptotic process

Inferred from Biological aspect of Ancestor. Source: RefGenome

negative regulation of apoptotic process involved in outflow tract morphogenesis

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: BHF-UCL

neural crest cell development

Inferred from electronic annotation. Source: Ensembl

ossification

Inferred from Biological aspect of Ancestor. Source: RefGenome

paraxial mesodermal cell fate commitment

Inferred from Biological aspect of Ancestor. Source: RefGenome

patterning of blood vessels

Inferred from Biological aspect of Ancestor. Source: RefGenome

positive regulation of cell adhesion mediated by integrin

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of cell migration involved in sprouting angiogenesis

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of endothelial cell migration

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of transcription, DNA-templated

Inferred from direct assay PubMed 16081467Ref.1. Source: UniProtKB

positive regulation of vascular wound healing

Inferred from sequence or structural similarity. Source: BHF-UCL

regulation of blood vessel size

Inferred from Biological aspect of Ancestor. Source: RefGenome

regulation of organ growth

Inferred from Biological aspect of Ancestor. Source: RefGenome

regulation of sequence-specific DNA binding transcription factor activity

Inferred from Biological aspect of Ancestor. Source: RefGenome

response to hormone

Inferred from direct assay PubMed 16456100. Source: UniProtKB

somitogenesis

Inferred from Biological aspect of Ancestor. Source: RefGenome

transcription from RNA polymerase II promoter

Inferred from Biological aspect of Ancestor. Source: GOC

ureteric bud development

Inferred from Biological aspect of Ancestor. Source: RefGenome

vascular endothelial growth factor receptor signaling pathway

Inferred from Biological aspect of Ancestor. Source: RefGenome

ventricular cardiac muscle tissue morphogenesis

Inferred from Biological aspect of Ancestor. Source: RefGenome

   Cellular_componentnucleus

Inferred from direct assay PubMed 11562355PubMed 16081467. Source: UniProtKB

transcription factor complex

Inferred from Biological aspect of Ancestor. Source: RefGenome

   Molecular_functionDNA binding, bending

Inferred from Biological aspect of Ancestor. Source: RefGenome

RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription

Inferred from direct assay PubMed 20956529. Source: BHF-UCL

RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity

Inferred from Biological aspect of Ancestor. Source: RefGenome

chromatin DNA binding

Inferred from direct assay PubMed 16456100. Source: UniProtKB

double-stranded DNA binding

Inferred from Biological aspect of Ancestor. Source: RefGenome

sequence-specific DNA binding

Inferred from direct assay PubMed 16081467. Source: UniProtKB

sequence-specific DNA binding transcription factor activity

Inferred from direct assay Ref.1. Source: UniProtKB

transcription factor binding

Inferred from Biological aspect of Ancestor. Source: RefGenome

transcription regulatory region DNA binding

Inferred from sequence or structural similarity. Source: BHF-UCL

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 501501Forkhead box protein C2
PRO_0000091808

Regions

DNA binding71 – 16292Fork-head
Compositional bias163 – 1675Poly-Arg
Compositional bias387 – 39610His-rich
Compositional bias397 – 41418Pro-rich

Amino acid modifications

Modified residue2151Phosphoserine Ref.9
Modified residue2191Phosphoserine Ref.8 Ref.9 Ref.13
Modified residue2321Phosphoserine Ref.9 Ref.11 Ref.13
Modified residue2351Phosphoserine Ref.7
Modified residue2401Phosphoserine Ref.6 Ref.7 Ref.9 Ref.11 Ref.12 Ref.13
Modified residue2471Phosphothreonine Ref.13
Modified residue2511Phosphoserine Ref.13
Modified residue2811Phosphoserine Ref.13
Modified residue2881Phosphoserine Ref.9 Ref.13
Modified residue3671Phosphoserine Ref.13

Natural variations

Natural variant1251S → L in LYD. Ref.15
VAR_018418
Natural variant1911S → F. Ref.2
Corresponds to variant rs78018668 [ dbSNP | Ensembl ].
VAR_060950

Secondary structure

............... 501
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q99958 [UniParc].

Last modified May 1, 1997. Version 1.
Checksum: F66513878EDC3A87

FASTA50153,719
        10         20         30         40         50         60 
MQARYSVSDP NALGVVPYLS EQNYYRAAGS YGGMASPMGV YSGHPEQYSA GMGRSYAPYH 

        70         80         90        100        110        120 
HHQPAAPKDL VKPPYSYIAL ITMAIQNAPE KKITLNGIYQ FIMDRFPFYR ENKQGWQNSI 

       130        140        150        160        170        180 
RHNLSLNECF VKVPRDDKKP GKGSYWTLDP DSYNMFENGS FLRRRRRFKK KDVSKEKEER 

       190        200        210        220        230        240 
AHLKEPPPAA SKGAPATPHL ADAPKEAEKK VVIKSEAASP ALPVITKVET LSPESALQGS 

       250        260        270        280        290        300 
PRSAASTPAG SPDGSLPEHH AAAPNGLPGF SVENIMTLRT SPPGGELSPG AGRAGLVVPP 

       310        320        330        340        350        360 
LALPYAAAPP AAYGQPCAQG LEAGAAGGYQ CSMRAMSLYT GAERPAHMCV PPALDEALSD 

       370        380        390        400        410        420 
HPSGPTSPLS ALNLAAGQEG ALAATGHHHQ HHGHHHPQAP PPPPAPQPQP TPQPGAAAAQ 

       430        440        450        460        470        480 
AASWYLNHSG DLNHLPGHTF AAQQQTFPNV REMFNSHRLG IENSTLGESQ VSGNASCQLP 

       490        500 
YRSTPPLYRH AAPYSYDCTK Y 

« Hide

References

« Hide 'large scale' references
[1]"Isolation of the mouse (MFH-1) and human (FKHL 14) mesenchyme fork head-1 genes reveals conservation of their gene and protein structures."
Miura N., Iida K., Kakinuma H., Yang X.-L., Sugiyama T.
Genomics 41:489-492(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION.
[2]NIEHS SNPs program
Submitted (JUN-2009) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT PHE-191.
[3]"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].
[4]"Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome."
Fang J., Dagenais S.L., Erickson R.P., Arlt M.F., Glynn M.W., Gorski J.L., Seaver L.H., Glover T.W.
Am. J. Hum. Genet. 67:1382-1388(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN LMPH2.
[5]"Truncating mutations in FOXC2 cause multiple lymphedema syndromes."
Finegold D.N., Kimak M.A., Lawrence E.C., Levinson K.L., Cherniske E.M., Pober B.R., Dunlap J.W., Ferrell R.E.
Hum. Mol. Genet. 10:1185-1189(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN LYMPHEDEMA SYNDROMES.
[6]"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.
Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-240, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[7]"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis."
Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III
J. Proteome Res. 7:1346-1351(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-235 AND SER-240, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[8]"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-219, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[9]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-215; SER-219; SER-232; SER-240 AND SER-288, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[10]"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach."
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.
Anal. Chem. 81:4493-4501(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-232 AND SER-240, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[12]"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-240, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]"Phosphorylation regulates FOXC2-mediated transcription in lymphatic endothelial cells."
Ivanov K.I., Agalarov Y., Valmu L., Samuilova O., Liebl J., Houhou N., Maby-El Hajjami H., Norrmen C., Jaquet M., Miura N., Zangger N., Yla-Herttuala S., Delorenzi M., Petrova T.V.
Mol. Cell. Biol. 33:3749-3761(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-219; SER-232; SER-240; THR-247; SER-251; SER-281; SER-288 AND SER-367, IDENTIFICATION BY MASS SPECTROMETRY.
[14]"Solution structure and dynamics of the DNA-binding domain of the adipocyte-transcription factor FREAC-11."
van Dongen M.J., Cederberg A., Carlsson P., Enerback S., Wikstrom M.
J. Mol. Biol. 296:351-359(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 70-162.
[15]"Analysis of lymphoedema-distichiasis families for FOXC2 mutations reveals small insertions and deletions throughout the gene."
Bell R., Brice G., Child A.H., Murday V.A., Mansour S., Sandy C.J., Collin J.R.O., Brady A.F., Callen D.F., Burnand K., Mortimer P., Jeffery S.
Hum. Genet. 108:546-551(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT LYD LEU-125.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
Y08223 Genomic DNA. Translation: CAA69400.1.
GQ282998 Genomic DNA. Translation: ACS83751.1.
BC113437 mRNA. Translation: AAI13438.1.
BC113439 mRNA. Translation: AAI13440.1.
CCDSCCDS10958.1.
RefSeqNP_005242.1. NM_005251.2.
UniGeneHs.436448.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1D5VNMR-A70-162[»]
ProteinModelPortalQ99958.
SMRQ99958. Positions 70-162.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108592. 2 interactions.
IntActQ99958. 2 interactions.
STRING9606.ENSP00000326371.

PTM databases

PhosphoSiteQ99958.

Polymorphism databases

DMDM3024149.

Proteomic databases

MaxQBQ99958.
PaxDbQ99958.
PRIDEQ99958.

Protocols and materials databases

DNASU2303.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000320354; ENSP00000326371; ENSG00000176692.
GeneID2303.
KEGGhsa:2303.
UCSCuc002fjq.3. human.

Organism-specific databases

CTD2303.
GeneCardsGC16P086600.
GeneReviewsFOXC2.
HGNCHGNC:3801. FOXC2.
MIM153200. phenotype.
153300. phenotype.
153400. phenotype.
602402. gene+phenotype.
neXtProtNX_Q99958.
Orphanet33001. Lymphedema - distichiasis.
PharmGKBPA28218.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5025.
HOGENOMHOG000007939.
HOVERGENHBG051640.
InParanoidQ99958.
KOK09396.
OMALNHLPGH.
OrthoDBEOG7C8GHD.
PhylomeDBQ99958.
TreeFamTF316127.

Enzyme and pathway databases

SignaLinkQ99958.

Gene expression databases

ArrayExpressQ99958.
BgeeQ99958.
CleanExHS_FOXC2.
GenevestigatorQ99958.

Family and domain databases

Gene3D1.10.10.10. 1 hit.
InterProIPR001766. TF_fork_head.
IPR018122. TF_fork_head_CS.
IPR011991. WHTH_DNA-bd_dom.
[Graphical view]
PfamPF00250. Fork_head. 1 hit.
[Graphical view]
PRINTSPR00053. FORKHEAD.
SMARTSM00339. FH. 1 hit.
[Graphical view]
PROSITEPS00657. FORK_HEAD_1. 1 hit.
PS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ99958.
GeneWikiFOXC2.
GenomeRNAi2303.
NextBio9351.
PROQ99958.
SOURCESearch...

Entry information

Entry nameFOXC2_HUMAN
AccessionPrimary (citable) accession number: Q99958
Secondary accession number(s): C6KMR9, Q14DA6
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: May 1, 1997
Last modified: July 9, 2014
This is version 140 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 16

Human chromosome 16: entries, gene names and cross-references to MIM