Q99958 (FOXC2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

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	501 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

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 (LMPH2) [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.4 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 (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.13
Sequence similarities	Contains 1 fork-head DNA-binding domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	DNA-binding
Molecular function	Activator Developmental protein
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Uncategorized	promoter binding Inferred from Biological aspect of Ancestor. Source: RefGenome specific RNA polymerase II transcription factor activity Inferred from Biological aspect of Ancestor. Source: RefGenome specific transcriptional repressor activity Inferred from Biological aspect of Ancestor. Source: RefGenome
Biological process	Notch signaling pathway Inferred from Biological aspect of Ancestor. Source: RefGenome anti-apoptosis 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 insulin receptor signaling pathway Inferred from direct assay. Source: UniProtKB lymphangiogenesis Inferred from mutant phenotype. Source: UniProtKB metanephros development Inferred from Biological aspect of Ancestor. Source: RefGenome negative regulation of transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: BHF-UCL neural crest cell fate commitment Inferred from Biological aspect of Ancestor. Source: RefGenome 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 transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: BHF-UCL 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 somitogenesis Inferred from Biological aspect of Ancestor. Source: RefGenome 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 vasculogenesis Inferred from Biological aspect of Ancestor. Source: RefGenome ventricular cardiac muscle tissue morphogenesis Inferred from Biological aspect of Ancestor. Source: RefGenome
Cellular component	transcription factor complex Inferred from Biological aspect of Ancestor. Source: RefGenome
Molecular function	DNA binding, bending Inferred from Biological aspect of Ancestor. Source: RefGenome chromatin DNA binding Inferred from direct assay. Source: UniProtKB double-stranded DNA binding Inferred from Biological aspect of Ancestor. Source: RefGenome sequence-specific DNA binding Inferred from direct assay. Source: UniProtKB sequence-specific distal enhancer binding RNA polymerase II transcription factor activity Inferred from Biological aspect of Ancestor. Source: RefGenome 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 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

92

Fork-head

Compositional bias

163 – 167

5

Poly-Arg

Compositional bias

387 – 396

10

His-rich

Compositional bias

397 – 421

25

Ala/Pro-rich

Compositional bias

400 – 408

9

Poly-Pro

Compositional bias

416 – 422

7

Poly-Ala

Amino acid modifications

Modified residue

36

1

Phosphoserine Ref.10

Modified residue

215

1

Phosphoserine Ref.10

Modified residue

219

1

Phosphoserine Ref.7 Ref.9 Ref.10 Ref.11

Modified residue

232

1

Phosphoserine Ref.6 Ref.8 Ref.10 Ref.11

Modified residue

235

1

Phosphoserine Ref.8

Modified residue

240

1

Phosphoserine Ref.6 Ref.8 Ref.10 Ref.11

Modified residue

281

1

Phosphoserine Ref.8 Ref.10

Modified residue

288

1

Phosphoserine Ref.10

Natural variations

Natural variant

125

1

S → L in LYD. Ref.13

VAR_018418

Natural variant

191

1

S → F. Ref.2

VAR_060950

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

501

Helix Strand Turn

Details...

Helix

77 – 86

10

Beta strand

89 – 93

5

Helix

95 – 105

11

Helix

108 – 111

4

Helix

116 – 126

11

Beta strand

128 – 132

5

Beta strand

146 – 148

3

Sequences

	Sequence		Length	Mass (Da)
	Q99958 [UniParc]. Last modified May 1, 1997. Version 1. Checksum: F66513878EDC3A87	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

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]	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: 15489334] [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: 11078474] [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: 11371511] [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: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-232 AND SER-240, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[7]	"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: Cervix carcinoma.
[8]	"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. Tissue: Cervix carcinoma.
[9]	"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. Tissue: Cervix carcinoma.
[10]	"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. Tissue: Cervix carcinoma.
[11]	"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: 19413330] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-219; SER-232 AND SER-240, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[12]	"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.
[13]	"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.

Web resources

GeneReviews

NIEHS-SNPs

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.

IPI

IPI00019155.

RefSeq

NP_005242.1. NM_005251.2.

UniGene

Hs.436448.

3D structure databases

PDBe
RCSB PDB
PDBj

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

ProteinModelPortal

Q99958.

SMR

Q99958. Positions 70-162.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q99958. 1 interaction.

STRING

Q99958.

PTM databases

PhosphoSite

Q99958.

Polymorphism databases

DMDM

3024149.

Proteomic databases

PRIDE

Q99958.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000320354; ENSP00000326371; ENSG00000176692.

GeneID

2303.

KEGG

hsa:2303.

UCSC

uc002fjq.1. human.

Organism-specific databases

CTD

2303.

GeneCards

GC16P086600.

H-InvDB

HIX0038664.

HGNC

HGNC:3801. FOXC2.

MIM

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

neXtProt

NX_Q99958.

Orphanet

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

PharmGKB

PA28218.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG09491.

GeneTree

ENSGT00600000084180.

HOGENOM

HBG269707.

HOVERGEN

HBG051640.

InParanoid

Q99958.

OMA

MRAMSLY.

OrthoDB

EOG4MCX19.

PhylomeDB

Q99958.

Gene expression databases

ArrayExpress

Q99958.

Bgee

Q99958.

CleanEx

HS_FOXC2.

Genevestigator

Q99958.

GermOnline

ENSG00000176692. Homo sapiens.

Family and domain databases

InterPro

IPR001766. TF_fork_head.
IPR018122. TF_fork_head_CS.
IPR011991. WHTH_trsnscrt_rep_DNA-bd.
[Graphical view]

Gene3D

G3DSA:1.10.10.10. Wing_hlx_DNA_bd. 1 hit.

KO

K09396.

Pfam

PF00250. Fork_head. 1 hit.
[Graphical view]

PRINTS

PR00053. FORKHEAD.

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

NextBio

9351.

SOURCE

Search...

Entry information

Entry name

FOXC2_HUMAN

Accession

Primary (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:	January 25, 2012
This is version 112 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.