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Protein

Kit ligand

Gene

KITLG

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Ligand for the receptor-type protein-tyrosine kinase KIT. Plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. KITLG/SCF binding can activate several signaling pathways. Promotes phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and subsequent activation of the kinase AKT1. KITLG/SCF and KIT also transmit signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. KITLG/SCF and KIT promote activation of STAT family members STAT1, STAT3 and STAT5. KITLG/SCF and KIT promote activation of PLCG1, leading to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KITLG/SCF acts synergistically with other cytokines, probably interleukins.

GO - Molecular functioni

GO - Biological processi

  • cell adhesion Source: UniProtKB-KW
  • cell proliferation Source: ProtInc
  • embryonic hemopoiesis Source: DFLAT
  • male gonad development Source: UniProtKB
  • MAPK cascade Source: Reactome
  • positive regulation of DNA replication Source: BHF-UCL
  • positive regulation of protein kinase B signaling Source: Reactome
  • signal transduction Source: ProtInc

Keywordsi

Molecular functionGrowth factor
Biological processCell adhesion

Enzyme and pathway databases

ReactomeiR-HSA-1257604 PIP3 activates AKT signaling
R-HSA-1433557 Signaling by SCF-KIT
R-HSA-1433559 Regulation of KIT signaling
R-HSA-2219530 Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5673001 RAF/MAP kinase cascade
R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
SIGNORiP21583

Names & Taxonomyi

Protein namesi
Recommended name:
Kit ligand
Alternative name(s):
Mast cell growth factor
Short name:
MGF
Stem cell factor
Short name:
SCF
c-Kit ligand
Cleaved into the following chain:
Soluble KIT ligand
Short name:
sKITLG
Gene namesi
Name:KITLG
Synonyms:MGF, SCF
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000049130.13
HGNCiHGNC:6343 KITLG
MIMi184745 gene
neXtProtiNX_P21583

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

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini26 – 214ExtracellularSequence analysisAdd BLAST189
Transmembranei215 – 237HelicalSequence analysisAdd BLAST23
Topological domaini238 – 273CytoplasmicSequence analysisAdd BLAST36

Keywords - Cellular componenti

Cell membrane, Cell projection, Cytoplasm, Cytoskeleton, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Hyperpigmentation with or without hypopigmentation, familial progressive (FPHH)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age. Hyperpigmentation has variable intensity, and sometimes is associated with cafe-au-lait macules and larger hypopigmented ash-leaf macules.
See also OMIM:145250
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06323736N → S in FPHH; gain-of-function mutation; sKITLG reveales that the mutant Ser-36 sKITLG increases the content of the melanin by 109% compared with the wild-type sKITLG; tyrosinase activity is significantly increased by the mutant sKITLG compared to wild-type control. 1 PublicationCorresponds to variant dbSNP:rs121918653Ensembl.1
Deafness, congenital, unilateral or asymmetric (DCUA)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant form of non-syndromic, sensorineural deafness characterized by inability to hear affecting one ear. Some patients suffers from asymmetric, bilateral hearing loss.
See also OMIM:616697
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07622267 – 68HC → R in DCUA; loss of cell membrane association. 1 Publication2

Keywords - Diseasei

Deafness, Disease mutation, Non-syndromic deafness

Organism-specific databases

DisGeNETi4254
MalaCardsiKITLG
MIMi145250 phenotype
611664 phenotype
616697 phenotype
OpenTargetsiENSG00000049130
Orphaneti280628 Familial progressive hyper- and hypopigmentation
79146 Familial progressive hyperpigmentation
363494 Testicular non seminomatous germ cell tumor
PharmGKBiPA30129

Chemistry databases

ChEMBLiCHEMBL2346489

Polymorphism and mutation databases

BioMutaiKITLG
DMDMi134289

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 25Add BLAST25
ChainiPRO_000003191326 – 273Kit ligandAdd BLAST248
ChainiPRO_000040339126 – 190Soluble KIT ligandAdd BLAST165

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi29 ↔ 114
Disulfide bondi68 ↔ 163
Glycosylationi90N-linked (GlcNAc...) asparagine; partial1 Publication1
Glycosylationi118N-linked (GlcNAc...) asparagine; partial1 Publication1
Glycosylationi145N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi167O-linked (GalNAc...) serine1 Publication1
Glycosylationi168O-linked (GalNAc...) threonine1 Publication1
Glycosylationi180O-linked (GalNAc...) threonine1 Publication1
Glycosylationi195N-linked (GlcNAc...) asparagineSequence analysis1

Post-translational modificationi

A soluble form (sKITLG) is produced by proteolytic processing of isoform 1 in the extracellular domain.1 Publication
Found in two differentially glycosylated forms, LMW-SCF and HMW-SCF. LMW-SCF is fully N-glycosylated at Asn-145, partially N-glycosylated at Asn-90, O-glycosylated at Ser-167, Thr-168 and Thr-180, and not glycosylated at Asn-97 or Asn-118. HMW-SCF is N-glycosylated at Asn-118, Asn-90 and Asn-145, O-glycosylated at Ser-167, Thr-168 and Thr-180, and not glycosylated at Asn-97.1 Publication
A soluble form exists as a cleavage product of the extracellular domain.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei97Not glycosylated1

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

MaxQBiP21583
PaxDbiP21583
PeptideAtlasiP21583
PRIDEiP21583

PTM databases

iPTMnetiP21583
PhosphoSitePlusiP21583

Miscellaneous databases

PMAP-CutDBiP21583

Expressioni

Developmental stagei

Acts in the early stages of hematopoiesis.

Gene expression databases

BgeeiENSG00000049130
CleanExiHS_KITLG
ExpressionAtlasiP21583 baseline and differential
GenevisibleiP21583 HS

Organism-specific databases

HPAiHPA070395

Interactioni

Subunit structurei

Homodimer, non-covalently linked (Probable). Heterotetramer with KIT, binding two KIT molecules; thereby mediates KIT dimerization and subsequent activation by autophosphorylation.Curated1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
KITP107212EBI-1379527,EBI-1379503

GO - Molecular functioni

Protein-protein interaction databases

BioGridi110410, 9 interactors
IntActiP21583, 2 interactors
STRINGi9606.ENSP00000228280

Chemistry databases

BindingDBiP21583

Structurei

Secondary structure

1273
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi30 – 32Combined sources3
Helixi37 – 46Combined sources10
Beta strandi53 – 56Combined sources4
Turni59 – 63Combined sources5
Helixi66 – 68Combined sources3
Helixi70 – 85Combined sources16
Beta strandi92 – 94Combined sources3
Helixi97 – 114Combined sources18
Beta strandi120 – 122Combined sources3
Beta strandi132 – 135Combined sources4
Helixi137 – 149Combined sources13
Turni150 – 152Combined sources3
Beta strandi157 – 160Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1EXZX-ray2.30A/B/C/D26-166[»]
1SCFX-ray2.20A/B/C/D1-273[»]
2E9WX-ray3.50C/D26-166[»]
DisProtiDP00917
ProteinModelPortaliP21583
SMRiP21583
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP21583

Family & Domainsi

Sequence similaritiesi

Belongs to the SCF family.Curated

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IF3Y Eukaryota
ENOG410XYQR LUCA
GeneTreeiENSGT00390000018272
HOVERGENiHBG036146
InParanoidiP21583
KOiK05461
OMAiVKTKGIC
OrthoDBiEOG091G0I23
PhylomeDBiP21583
TreeFamiTF330811

Family and domain databases

InterProiView protein in InterPro
IPR009079 4_helix_cytokine-like_core
IPR003452 SCF
PANTHERiPTHR11574 PTHR11574, 1 hit
PfamiView protein in Pfam
PF02404 SCF, 1 hit
PIRSFiPIRSF015599 SCF, 1 hit
SUPFAMiSSF47266 SSF47266, 1 hit

Sequences (3)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P21583-1) [UniParc]FASTAAdd to basket
Also known as: SCF248

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MKKTQTWILT CIYLQLLLFN PLVKTEGICR NRVTNNVKDV TKLVANLPKD
60 70 80 90 100
YMITLKYVPG MDVLPSHCWI SEMVVQLSDS LTDLLDKFSN ISEGLSNYSI
110 120 130 140 150
IDKLVNIVDD LVECVKENSS KDLKKSFKSP EPRLFTPEEF FRIFNRSIDA
160 170 180 190 200
FKDFVVASET SDCVVSSTLS PEKDSRVSVT KPFMLPPVAA SSLRNDSSSS
210 220 230 240 250
NRKAKNPPGD SSLHWAAMAL PALFSLIIGF AFGALYWKKR QPSLTRAVEN
260 270
IQINEEDNEI SMLQEKEREF QEV
Length:273
Mass (Da):30,899
Last modified:May 1, 1991 - v1
Checksum:i19FD362CB59C6607
GO
Isoform 2 (identifier: P21583-2) [UniParc]FASTAAdd to basket
Also known as: SCF220

The sequence of this isoform differs from the canonical sequence as follows:
     174-202: DSRVSVTKPFMLPPVAASSLRNDSSSSNR → G

Show »
Length:245
Mass (Da):27,867
Checksum:i937AEA64456DF4FA
GO
Isoform 3 (identifier: P21583-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-35: Missing.
     36-43: NVKDVTKL → MPSCLAAQ

Note: No experimental confirmation available.
Show »
Length:238
Mass (Da):26,667
Checksum:i7D6B1E487BE3709B
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti55L → S in AAD22048 (PubMed:10049787).Curated1
Sequence conflicti55L → S in AAK92486 (Ref. 4) Curated1
Sequence conflicti128K → R in AAD22048 (PubMed:10049787).Curated1
Sequence conflicti128K → R in AAK92486 (Ref. 4) Curated1
Sequence conflicti134L → F in AAD22048 (PubMed:10049787).Curated1
Sequence conflicti134L → F in AAK92486 (Ref. 4) Curated1

Polymorphismi

Genetic variants in KITLG define the skin/hair/eye pigmentation variation locus 7 (SHEP7) [MIMi:611664]. Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair.
A non-coding SNP (dbSNP:rs12821256) has been shown to be associated with classic blond hair color in Europeans. This SNP is located 350 kb upstream from KITLG, in an enhancer specifically active in the hair follicle environment. It alters a LEF1 binding site, reducing LEF1 responsiveness in cultured keratinocytes. This SNP is not associated with eye pigmentation. It is most prevalent in Northern Europe (PubMed:24880339).1 Publication

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06323736N → S in FPHH; gain-of-function mutation; sKITLG reveales that the mutant Ser-36 sKITLG increases the content of the melanin by 109% compared with the wild-type sKITLG; tyrosinase activity is significantly increased by the mutant sKITLG compared to wild-type control. 1 PublicationCorresponds to variant dbSNP:rs121918653Ensembl.1
Natural variantiVAR_04265254T → A. Corresponds to variant dbSNP:rs3741457Ensembl.1
Natural variantiVAR_07622267 – 68HC → R in DCUA; loss of cell membrane association. 1 Publication2
Natural variantiVAR_076223104L → V Found in a patient with Waardenburg syndrome type 2 (WS2) and hearing loss; unknown pathological significance; reduces secretion. 1 PublicationCorresponds to variant dbSNP:rs864309655Ensembl.1
Natural variantiVAR_063238210D → Y. Corresponds to variant dbSNP:rs41283112Ensembl.1
Natural variantiVAR_042653232F → Y. Corresponds to variant dbSNP:rs12721563Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0327621 – 35Missing in isoform 3. 1 PublicationAdd BLAST35
Alternative sequenceiVSP_03276336 – 43NVKDVTKL → MPSCLAAQ in isoform 3. 1 Publication8
Alternative sequenceiVSP_006022174 – 202DSRVS…SSSNR → G in isoform 2. 6 PublicationsAdd BLAST29

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M59964 mRNA Translation: AAA85450.1
AF119835 mRNA Translation: AAD22048.1
AF400436 mRNA Translation: AAK92485.1
AF400437 mRNA Translation: AAK92486.1
AK290319 mRNA Translation: BAF83008.1
AK293002 mRNA Translation: BAF85691.1
CR749222 mRNA Translation: CAH18078.1
CH471054 Genomic DNA Translation: EAW97417.1
BC069733 mRNA Translation: AAH69733.1
BC069783 mRNA Translation: AAH69783.1
BC069797 mRNA Translation: AAH69797.1
BC074725 mRNA Translation: AAH74725.1
BC126166 mRNA Translation: AAI26167.1
BC143899 mRNA Translation: AAI43900.1
S42571 mRNA Translation: AAB22846.2
CCDSiCCDS31867.1 [P21583-2]
CCDS31868.1 [P21583-1]
PIRiA35974
B61190
S29052
RefSeqiNP_000890.1, NM_000899.4 [P21583-1]
NP_003985.2, NM_003994.5 [P21583-2]
UniGeneiHs.1048
Hs.661108

Genome annotation databases

EnsembliENST00000228280; ENSP00000228280; ENSG00000049130 [P21583-1]
ENST00000347404; ENSP00000054216; ENSG00000049130 [P21583-2]
GeneIDi4254
KEGGihsa:4254
UCSCiuc001tav.4 human [P21583-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiSCF_HUMAN
AccessioniPrimary (citable) accession number: P21583
Secondary accession number(s): A0AV09
, A8K2Q4, B7ZLM4, Q16487, Q68DZ2, Q7M4N8, Q9UQK7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: May 1, 1991
Last modified: April 25, 2018
This is version 172 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome
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Main funding by: National Institutes of Health