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Protein

Forkhead box protein C1

Gene

Foxc1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

DNA-binding transcriptional factor that plays a role in a broad range of cellular and developmental processes such as eye, bones, cardiovascular, kidney and skin development (PubMed:9635428, PubMed:9106663, PubMed:10479458, PubMed:10395790, PubMed:11562355, PubMed:18187037, PubMed:19668217, PubMed:22493429, PubMed:24590069, PubMed:25808752, PubMed:28223138). Acts either as a transcriptional activator or repressor (PubMed:28223138). Binds to the consensus binding site 5'-[G/C][A/T]AAA[T/C]AA[A/C]-3' in promoter of target genes (PubMed:25808752). Upon DNA-binding, promotes DNA bending. Acts as a transcriptional coactivator (PubMed:25808752). Stimulates Indian hedgehog (Ihh)-induced target gene expression mediated by the transcription factor GLI2, and hence regulates endochondral ossification (PubMed:25808752). Acts also as a transcriptional coregulator by increasing DNA-binding capacity of GLI2 in breast cancer cells. Regulates FOXO1 through binding to a conserved element, 5'-GTAAACAAA-3' in its promoter region, implicating FOXC1 as an important regulator of cell viability and resistance to oxidative stress in the eye (By similarity). Cooperates with transcription factor FOXC2 in regulating expression of genes that maintain podocyte integrity (PubMed:28223138). Promotes cell growth inhibition by stopping the cell cycle in the G1 phase through TGFB1-mediated signals. Involved in epithelial-mesenchymal transition (EMT) induction by increasing cell proliferation, migration and invasion (By similarity). Involved in chemokine CXCL12-induced endothelial cell migration through the control of CXCR4 expression (PubMed:18187037). Plays a role in the gene regulatory network essential for epidermal keratinocyte terminal differentiation (By similarity). Essential developmental transcriptional factor required for mesoderm-derived tissues formation, such as the somites, skin, bone and cartilage (PubMed:9106663, PubMed:10479458, PubMed:10395790, PubMed:10704385, PubMed:11562355, PubMed:15196959). Positively regulates CXCL12 and stem cell factor expression in bone marrow mesenchymal progenitor cells, and hence plays a role in the development and maintenance of mesenchymal niches for haematopoietic stem and progenitor cells (HSPC) (PubMed:24590069). Plays a role in corneal transparency by preventing both blood vessel and lymphatic vessel growth during embryonic development in a VEGF-dependent manner (PubMed:22171010). May function as a tumor suppressor (By similarity).By similarity14 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi77 – 168Fork-headPROSITE-ProRule annotationAdd BLAST92

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionActivator, Developmental protein, DNA-binding, Repressor
Biological processAngiogenesis, Transcription, Transcription regulation

Names & Taxonomyi

Protein namesi
Recommended name:
Forkhead box protein C1
Alternative name(s):
Forkhead-related protein FKHL7
Forkhead-related transcription factor 3
Short name:
FREAC-3
Mesoderm/mesenchyme forkhead 1
Short name:
MF-1
Transcription factor FKH-1
Gene namesi
Name:Foxc1
Synonyms:Fkh1, Fkhl7, Freac3, Mf1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 13

Organism-specific databases

MGIiMGI:1347466 Foxc1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Disruption phenotypei

Embryos die pre- and perinatally with haemorrhagic hydrocephalus and calvarial defects, beginning at 13.5 dpc (PubMed:9635428, PubMed:10479458, PubMed:19668217). Mutants that survive to later stages exhibit multiple craniofacial and vertebral defects characterized by disorganized rib fusion, absence of chondrocytes proliferation and ossification (PubMed:9106663, PubMed:25808752). Show abnormal cerebellar development with an enlarged fourth ventricle roof plate at 12.5 dpc and a disorganized cerebellar rhombic lip (PubMed:19668217). Show eye formation abnormalities: the lens remains attached to the cornea, both the anterior chamber and the corneal endothelium are absent, the corneal stroma is thicker, the arrangement of mesenchyme cells are disorganized and the corneal endothelial cells do not differentiate (PubMed:10395790). Show cardiovascular defects including persistent truncus arteriosus, ventricular septal defect, coarctation of the aortic arch, and aortic and pulmonary valve dysplasia (PubMed:10479458). Show abnormal kidney and ureter development, including duplex kidneys connecting to double ureters (PubMed:10704385). Show a decrease in hedgehog-induced genes expression levels involved in endochondral ossification (PubMed:25808752). Double knockout of FOXC1 and FOXC2 genes in mice embryos die around 8-9.5 dpc and show profound abnormalities in the first and second branchial arches, the early remodeling of blood vessels, a complete absence of segmented paraxial mesoderm, and the presence of ectopic and disorganized mesonephric kidney tubules (PubMed:11562355, PubMed:15196959). Mice with conditional knockout of both FOXC1 and FOXC2 genes in adult mice show renal tubular damage with protein reabsorption droplets, tubular dilation and proteinaceous casts and show also altered expression levels for several genes involved in the differentiation of podocytes (PubMed:28223138). Display also podocyte degeneration characterized with microvillous transformation, podocyte foot process effacement and irregular thickness of the glomerular basement membrane (PubMed:28223138). Podocyte-cell-specific conditional knockout of both FOXC1 and FOXC2 genes in adult mice show reabsorption droplets, tubular dilation and proteinaceous casts (PubMed:28223138). Endothelial-specific conditional knockout mice show a significant reduction in CXCR4 expression as well as in chemokine CXCL12-induced endothelial cell migration (PubMed:18187037). Limb bud mesenchymal-specific conditional knockout mice display strong reduction in haematopoietic stem and progenitor cells, the presence of adipocytes in marrow cavities (yellow adipose marrow) instead of CXCL12-abundant reticular (CAR) cells and die around 6 weeks of age with haemorrhagic hydrocephalus and calvarial defects (PubMed:24590069). CAR cell-specific conditional knockout mice are viable and die without hydrocephalus defects, but show a reduction in haematopoietic stem and progenitor cells (HSPCs) and most marrow cavities are filled with adipocytes (PubMed:24590069). Adult widespread cell-specific conditional knockout mice show a reduction in haematopoietic stem and progenitor cells (HSPCs), with only occasional adipocytes present in marrow cavities (PubMed:24590069). Neural crest (NC)-specific conditional knockout mice die postnatally with hydrocephalus and craniofacial abnormalities comparable to those seen in conventional knockout mice; embryos display pupillary abnormalities, with impaired collagen formation in the corneal stroma and aberrant vessel growth in the normally avascular corneas (PubMed:22171010).13 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi6 – 9SVSS → AVAA: No effect on sumoylation; when associated with A-237; A-243; A-320 and A-521. 1 Publication4
Mutagenesisi112F → S: Inhibits interaction with GLI2. Decreased nuclear colocalization with GLI2. No effect on DNA-binding. Decreased Ihh-induced transcriptional activity and transcription coactivator activity with GLI2. 1 Publication1
Mutagenesisi229K → R: No effect on protein stability, inhibited sumoylation, increased transcriptional activity; when associated with R-258. 1 Publication1
Mutagenesisi237S → A: No effect on sumoylation; when associated with 6-A--A-9; A-243; A-320 and A-521. 1 Publication1
Mutagenesisi243S → A: No effect on sumoylation; when associated with 6-A--A-9; A-237; A-320 and A-521. 1 Publication1
Mutagenesisi258K → R: No effect on protein stability, inhibited sumoylation, increased transcriptional activity; when associated with R-229. 1 Publication1
Mutagenesisi320S → A: No effect on sumoylation; when associated with 6-A--A-9; A-237; A-243 and A-521. 1 Publication1
Mutagenesisi521S → A: No effect on sumoylation; when associated with 6-A--A-9; A-237; A-243 and A-320. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000918071 – 553Forkhead box protein C1Add BLAST553

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei237PhosphoserineCombined sources1 Publication1
Modified residuei243PhosphoserineCombined sources1 Publication1
Modified residuei274PhosphoserineBy similarity1
Modified residuei320Phosphoserine1 Publication1
Modified residuei521Phosphoserine1 Publication1

Post-translational modificationi

Phosphorylated (PubMed:22493429). Phosphorylated on Ser-274 in response to epidermal growth factor (EGF) in a ERK1/2 MAPK-dependent signaling pathway; phosphorylation contributes to its protein stability and transcriptional regulatory activity (By similarity).By similarity1 Publication
Sumoylated preferentially with SUMO2 or SUMO3. Desumoylated by SENP2.1 Publication
Ubiquitinated, leading to its proteasomal degradation.By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ61572
PaxDbiQ61572
PRIDEiQ61572

PTM databases

iPTMnetiQ61572
PhosphoSitePlusiQ61572

Expressioni

Tissue specificityi

Expressed in glomerular epithelial cells, the podocytes (PubMed:28223138). Expressed in a population of adipo-osteogenic progenitor cells, termed CXCL12-abundant reticular (CAR) cells (at protein level) (PubMed:24590069). Expressed in many embryonic tissues, including prechondrogenic mesenchyme, periocular mesenchyme, meninges, endothelial cells and kidney (PubMed:9767123). Detected in adult brain, heart, kidney, adrenal gland, lung and testis, with lower levels in stomach, spleen and thymus (PubMed:9767123). Expressed in endothelial cells (PubMed:18187037). Expressed in the mesenchyme adjacent to the developing cerebellum (PubMed:19668217). Expressed in the sternum and rib cartilage (PubMed:25808752). Expressed in growth plate chondrocytes (PubMed:25808752).6 Publications

Developmental stagei

Expressed in the anterior presomitic mesoderm (PSM) and somites at 9.5 dpc. Expressed in endothelial and smooth muscle cells of blood vessels at 9.5 dpc (PubMed:11562355). Expressed in growth plate chondrocytes and perichondrial cells at 13.5 dpc (at protein level) (PubMed:25808752). Expressed in non-notochordal mesoderm surrounding the node and notochord at 7.5 dpc (PubMed:9106663). Expressed in anterior presomitic mesoderm adjacent to somites, in the somites, and in the cephalic mesoderm at 8.5 and 9.5 dpc (PubMed:9106663). Detected weakly in yolk sac at 9.5 dpc (PubMed:11562355). Expressed in presumptive intermediate mesoderm, as well as in the presomitic mesoderm and somites at 8.5 and 9.5 dpc (PubMed:10704385). Expressed in the metanephric mesenchyme of the kidney at 10.5 and 12.5 dpc (PubMed:10704385). Expressed during the developing cardiovascular system (PubMed:10479458). Expressed in the branchial arches and mesenchymal cells surrounding the eye at 10.5 dpc (PubMed:9106663). Expressed in nasal processes, corneal mesenchyme cells, branchial arches, blood vessels and endocardium at 11.5 dpc (PubMed:9106663, PubMed:10395790). Expressed in cells located in the presumptive anterior segment that are fated to contribute to the corneal endothelium or stroma, as well as within cells located at the periphery of the optic cup at 11.5 dpc (PubMed:16449236). Expressed in periocular mesenchyme cells at 11.5, 12.5 and 16.5 dpc (PubMed:10395790, PubMed:16449236). Expressed in developing limb buds at 12.5 dpc (PubMed:25808752). Expressed in chondrocytes at 15 dpc (PubMed:25808752). Expressed in the trabecular meshwork cells, the sclera, the conjunctival epithelium and the corneal epithelium at 16.5 dpc (PubMed:10395790). Strongly expressed in adipo-osteogenic progenitor cells (CXCL12-abundant reticular (CAR) cells) at 16.5 dpc and at birth (PubMed:24590069).8 Publications

Gene expression databases

BgeeiENSMUSG00000050295 Expressed in 285 organ(s), highest expression level in stria vascularis of cochlear duct
CleanExiMM_FOXC1
GenevisibleiQ61572 MM

Interactioni

Subunit structurei

Monomer. Interacts with C1QBP (By similarity). Interacts (via N-terminus) with GLI2 (via C-terminal internal region); this interaction is direct and increases GLI2 DNA-binding and transcriptional activity through a smoothened (SMO)-independent Hedgehog (Hh) signaling pathway (PubMed:26565916, PubMed:25808752). Interacts (via C-terminus domain) with PITX2 (via homeobox domain) (By similarity). Interacts with FLNA and PBX1 (By similarity).By similarity2 Publications

GO - Molecular functioni

Protein-protein interaction databases

IntActiQ61572, 2 interactors
STRINGi10090.ENSMUSP00000052196

Structurei

3D structure databases

ProteinModelPortaliQ61572
SMRiQ61572
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 51Required for transcriptional activationBy similarityAdd BLAST51
Regioni217 – 366Required for transcriptional inhibitionBy similarityAdd BLAST150
Regioni466 – 553Required for transcriptional activationBy similarityAdd BLAST88

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi78 – 93Nuclear localization signal 1 (NLS 1)By similarityAdd BLAST16
Motifi168 – 176Nuclear localization signal 2 (NLS 2)By similarity9

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi28 – 33Poly-Ala6
Compositional biasi169 – 173Poly-Arg5
Compositional biasi194 – 197Poly-Pro4
Compositional biasi264 – 274Poly-SerAdd BLAST11
Compositional biasi375 – 386Poly-GlyAdd BLAST12
Compositional biasi444 – 451Poly-Ser8
Compositional biasi453 – 456Poly-Gly4
Compositional biasi486 – 496Poly-AlaAdd BLAST11

Phylogenomic databases

eggNOGiKOG2294 Eukaryota
COG5025 LUCA
GeneTreeiENSGT00760000118904
HOGENOMiHOG000007939
HOVERGENiHBG051640
InParanoidiQ61572
KOiK09396
OMAiGRLTSWY
OrthoDBiEOG091G0HW9
TreeFamiTF316127

Family and domain databases

CDDicd00059 FH, 1 hit
Gene3Di1.10.10.10, 1 hit
InterProiView protein in InterPro
IPR001766 Fork_head_dom
IPR018122 TF_fork_head_CS_1
IPR030456 TF_fork_head_CS_2
IPR036388 WH-like_DNA-bd_sf
IPR036390 WH_DNA-bd_sf
PfamiView protein in Pfam
PF00250 Forkhead, 1 hit
PRINTSiPR00053 FORKHEAD
SMARTiView protein in SMART
SM00339 FH, 1 hit
SUPFAMiSSF46785 SSF46785, 1 hit
PROSITEiView protein in PROSITE
PS00657 FORK_HEAD_1, 1 hit
PS00658 FORK_HEAD_2, 1 hit
PS50039 FORK_HEAD_3, 1 hit

Sequencei

Sequence statusi: Complete.

Q61572-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MQARYSVSSP NSLGVVPYLG GEQSYYRAAA AAAGGGYTAM PAPMSVYSHP
60 70 80 90 100
AHAEQYPGSM ARAYGPYTPQ PQPKDMVKPP YSYIALITMA IQNAPDKKIT
110 120 130 140 150
LNGIYQFIMD RFPFYRDNKQ GWQNSIRHNL SLNECFVKVP RDDKKPGKGS
160 170 180 190 200
YWTLDPDSYN MFENGSFLRR RRRFKKKDAV KDKEEKGRLH LQEPPPPQAG
210 220 230 240 250
RQPAPAPPEQ AEGSAPGPQP PPVRIQDIKT ENGTCPSPPQ PLSPAAALGS
260 270 280 290 300
GSAATVPKIE SPDSSSSSLS SGSSPPGSLP SARPLSLDAA EPAPPPQPAP
310 320 330 340 350
PPHHSQGFSV DNIMTSLRGS PQGSAAELGS GLLASAAASS RAGIAPPLAL
360 370 380 390 400
GAYSPGQSSL YSSPCSQSSS AGSSGGGGGG GGGGGGSSSA AGTGGAATYH
410 420 430 440 450
CNLQAMSLYA AGERGGHLQG PAGGAGSAAV DDPLPDYSLP PATSSSSSSL
460 470 480 490 500
SHGGGGQEAS HHPASHQGRL TSWYLNQAGG DLGHLASAAA AAAAAGYPGQ
510 520 530 540 550
QQNFHSVREM FESQRIGLNN SPVNGNSSCQ MAFPASQSLY RTSGAFVYDC

SKF
Length:553
Mass (Da):56,940
Last modified:July 27, 2011 - v3
Checksum:i3CDB14F69AA2F217
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti180 – 186VKDKEEK → KKEITFI in AAA03159 (PubMed:8375339).Curated7
Sequence conflicti496G → A in AAC24209 (PubMed:9635428).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF045017 mRNA Translation: AAC24209.1
AJ223298 Genomic DNA Translation: CAA11239.1
AK144420 mRNA Translation: BAE25882.1
BC052011 mRNA Translation: AAH52011.1
X71939 Genomic DNA Translation: CAA50741.1
L10406 mRNA Translation: AAA03159.1
CCDSiCCDS26425.1
PIRiI49674
RefSeqiNP_032618.2, NM_008592.2
UniGeneiMm.12949

Genome annotation databases

EnsembliENSMUST00000062292; ENSMUSP00000052196; ENSMUSG00000050295
GeneIDi17300
KEGGimmu:17300
UCSCiuc007pzp.1 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF045017 mRNA Translation: AAC24209.1
AJ223298 Genomic DNA Translation: CAA11239.1
AK144420 mRNA Translation: BAE25882.1
BC052011 mRNA Translation: AAH52011.1
X71939 Genomic DNA Translation: CAA50741.1
L10406 mRNA Translation: AAA03159.1
CCDSiCCDS26425.1
PIRiI49674
RefSeqiNP_032618.2, NM_008592.2
UniGeneiMm.12949

3D structure databases

ProteinModelPortaliQ61572
SMRiQ61572
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ61572, 2 interactors
STRINGi10090.ENSMUSP00000052196

PTM databases

iPTMnetiQ61572
PhosphoSitePlusiQ61572

Proteomic databases

MaxQBiQ61572
PaxDbiQ61572
PRIDEiQ61572

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000062292; ENSMUSP00000052196; ENSMUSG00000050295
GeneIDi17300
KEGGimmu:17300
UCSCiuc007pzp.1 mouse

Organism-specific databases

CTDi2296
MGIiMGI:1347466 Foxc1

Phylogenomic databases

eggNOGiKOG2294 Eukaryota
COG5025 LUCA
GeneTreeiENSGT00760000118904
HOGENOMiHOG000007939
HOVERGENiHBG051640
InParanoidiQ61572
KOiK09396
OMAiGRLTSWY
OrthoDBiEOG091G0HW9
TreeFamiTF316127

Miscellaneous databases

PROiPR:Q61572
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000050295 Expressed in 285 organ(s), highest expression level in stria vascularis of cochlear duct
CleanExiMM_FOXC1
GenevisibleiQ61572 MM

Family and domain databases

CDDicd00059 FH, 1 hit
Gene3Di1.10.10.10, 1 hit
InterProiView protein in InterPro
IPR001766 Fork_head_dom
IPR018122 TF_fork_head_CS_1
IPR030456 TF_fork_head_CS_2
IPR036388 WH-like_DNA-bd_sf
IPR036390 WH_DNA-bd_sf
PfamiView protein in Pfam
PF00250 Forkhead, 1 hit
PRINTSiPR00053 FORKHEAD
SMARTiView protein in SMART
SM00339 FH, 1 hit
SUPFAMiSSF46785 SSF46785, 1 hit
PROSITEiView protein in PROSITE
PS00657 FORK_HEAD_1, 1 hit
PS00658 FORK_HEAD_2, 1 hit
PS50039 FORK_HEAD_3, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiFOXC1_MOUSE
AccessioniPrimary (citable) accession number: Q61572
Secondary accession number(s): O88409, Q61582, Q9QWR9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: July 27, 2011
Last modified: November 7, 2018
This is version 151 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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