Forkhead box protein C2 - Homo sapiens (Human)

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Reviewed, UniProtKB/Swiss-Prot Q99958 (FOXC2_HUMAN)

Last modified July 7, 2009. Version 85. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Forkhead box protein C2
Alternative name(s):
    Forkhead-related protein FKHL14
    Transcription factor FKH-14
    Mesenchyme fork head protein 1
      Short name=MFH-1 protein

Gene names

Name:	FOXC2
Synonyms:	FKHL14, MFH1

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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Protein attributes

Sequence length	501 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Transcriptional activator. Might be involved in the formation of special mesenchymal tissues. Ref.1
Subcellular location	Nucleus Probable.
Involvement in disease	Defects in FOXC2 are the cause of lymphedema hereditary type 2 (LYH2) [MIM:153200]; also known as Meige lymphedema. Hereditary lymphedema is 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. Ref.3 Defects in FOXC2 are a cause of lymphedema-yellow nails (LYYN) [MIM:153300]. LYYN is 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. Defects in FOXC2 are a cause of lymphedema-distichiasis syndrome (LYD) [MIM:153400]. LYD is 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). Ref.11
Sequence similarities	Contains 1 fork-head DNA-binding domain.

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Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Disease	Disease mutation
Ligand	DNA-binding
Molecular function	Activator Developmental protein
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	insulin receptor signaling pathway Inferred from direct assay. Source: UniProtKB lymphangiogenesis Inferred from mutant phenotype. Source: UniProtKB transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleus Ref.1 Inferred from direct assay. Source: UniProtKB
Molecular function	chromatin DNA binding Inferred from direct assay. Source: UniProtKB sequence-specific DNA binding Inferred from direct assay. Source: UniProtKB transcription activator activity Ref.1 Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 501

501

Forkhead box protein C2

PRO_0000091808

Regions

DNA binding

71 – 162

Fork-head

Compositional bias

163 – 167

Poly-Arg

Compositional bias

387 – 396

His-rich

Compositional bias

397 – 421

Ala/Pro-rich

Compositional bias

400 – 408

Poly-Pro

Compositional bias

416 – 422

Poly-Ala

Amino acid modifications

Modified residue

Phosphoserine Ref.9

Modified residue

215

Phosphoserine Ref.9

Modified residue

219

Phosphoserine Ref.9 Ref.6 Ref.8

Modified residue

232

Phosphoserine Ref.9 Ref.5 Ref.7

Modified residue

235

Phosphoserine Ref.7

Modified residue

240

Phosphoserine Ref.9 Ref.5 Ref.7

Modified residue

281

Phosphoserine Ref.9 Ref.7

Modified residue

288

Phosphoserine Ref.9

Natural variations

Natural variant

125

S → L in LYD. Ref.11

VAR_018418

Secondary structure

501

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

Q99958-1 [UniParc].

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

501

53,719

        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

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References

	« Hide 'large scale' referencesShow '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: 9169153] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION.
[2]	"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].
[3]	"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: 11078474] [Abstract] Cited for: INVOLVEMENT IN LYH2.
[4]	"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: 11371511] [Abstract] Cited for: INVOLVEMENT IN LYMPHEDEMA SYNDROMES.
[5]	"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: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-232 AND SER-240, MASS SPECTROMETRY. Tissue: Epithelium.
[6]	"Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra." Yu L.-R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D. J. Proteome Res. 6:4150-4162(2007) [PubMed: 17924679] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-219, MASS SPECTROMETRY. Tissue: Epithelium.
[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: 18220336] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-232; SER-235; SER-240 AND SER-281, MASS SPECTROMETRY.
[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: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-219, MASS SPECTROMETRY.
[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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-36; SER-215; SER-219; SER-232; SER-240; SER-281 AND SER-288, MASS SPECTROMETRY.
[10]	"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: 10669593] [Abstract] Cited for: STRUCTURE BY NMR OF 70-162.
[11]	"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: 11499682] [Abstract] Cited for: VARIANT LYD LEU-125.
+	Additional computationally mapped references.

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Web resources

GeneReviews

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Cross-references

Sequence databases

Y08223 Genomic DNA. Translation: CAA69400.1.
BC113437 mRNA. Translation: AAI13438.1.
BC113439 mRNA. Translation: AAI13440.1.

IPI

IPI00019155.

RefSeq

NP_005242.1.

UniGene

Hs.436448

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1D5V	NMR	-	A	70-162	[»]

ModBase

Search...

PTM databases

PhosphoSite

Q99958.

Proteomic databases

PRIDE

Q99958.

Genome annotation databases

Ensembl

ENSG00000176692. Homo sapiens. [Contig view]

GeneID

2303.

KEGG

hsa:2303.

UCSC

uc002fjq.1. human.

Organism-specific databases

GeneCards

GC16P085158.

H-InvDB

HIX0038664.

HGNC

HGNC:3801. FOXC2.

MIM

153200. phenotype.
153300. phenotype.
153400. phenotype.
602402. gene+phenotype.

Orphanet

33001. Lymphedema - distichiasis.
2419. Lymphedema - ptosis.
662. Yellow nail syndrome.

PharmGKB

PA28218.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q99958.

HOVERGEN

Q99958.

OMA

Q99958. QQTFPNV.

Gene expression databases

ArrayExpress

Q99958.

Bgee

Q99958.

CleanEx

HS_FOXC2.

GermOnline

ENSG00000176692. Homo sapiens.

Family and domain databases

InterPro

IPR001766. TF_fork_head.
IPR018122. TF_fork_head_CS.
IPR011991. Wing_hlx_DNA_bd.
[Graphical view]

Gene3D

G3DSA:1.10.10.10. Wing_hlx_DNA_bd. 1 hit.

PANTHER

PTHR11829. Fork_box_protein. 1 hit.

Pfam

PF00250. Fork_head. 1 hit.
[Graphical view]

PRINTS

PR00053. FORKHEAD.

ProDom

PD000425. TF_Fork_head. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00339. FH. 1 hit.
[Graphical view]

PROSITE

PS00657. FORK_HEAD_1. 1 hit.
PS00658. FORK_HEAD_2. 1 hit.
PS50039. FORK_HEAD_3. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

9351.

SOURCE

Search...

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Entry information

Entry name

FOXC2_HUMAN

Accession

Primary (citable) accession number: Q99958
Secondary accession number(s): Q14DA6

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	May 1, 1997
Last modified:	July 7, 2009
This is version 85 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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