Atlas of Genetics and Cytogenetics in Oncology and Haematology


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KITLG (KIT ligand)

Identity

Other namesMGF
SCF
HGNC (Hugo) KITLG
LocusID (NCBI) 4254
Location 12q21.32
Location_base_pair Starts at 88886570 and ends at 88974250 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
Description KITLG/SCF is encoded by 10 exons (transcript variant b) and 9 exons (transcript variant a).
Transcription Transcript variant a: 5376 bp. The isoform a lacks the primary proteolytic cleavage site. As a result, the product encoded by this isoform is a membrane bound protein.
Transcript variant b: 5460 bp. The transcript isoform b contains the primary proteolytic-cleavage site and encodes a soluble product.
Although SCF exists as a monomer, Zhang et al. and Hsu et al. evidenced that dimerisation of SCF has been associated with KIT receptor activation and signal transduction. They demonstrated, through the crystal analysis, that the SCF dimer complex comprises of two SCF monomers with head-to-head interaction in order to form an elongated homo-dimer stabilised by both polar and non polar interactions.
Alternative splicing of the SCF transcript results in the inclusion or exclusion of an exon 6 which contains a proteolytic cleavage site, recognised by metalloprotease-9 enzyme that cleaves after an alanine residue (Ala 189) in the extracellular region, producing the 165-aminoacid soluble SCF. There are other proteases that have been suggested to be responsible for cleavage of membrane-bound SCF, as chymase-1, ADAM17 and ADAM33. The splice form that lacks the cleavage site and remains linked to the cell surface, is a result of the alternative splicing within exon 6 which skip the cleavage site for the metalloprotease-9.
In total, there are six alternative transcripts of SCF in humans, out of which four encode protein (http://www.ensembl.org).

Protein

 
  Adapted from Johan Lennartsson and Lars Rönnstrand, 2012.
Description The membrane bound form is a surface molecule of 248 aa, that includes 23 aa of the highly hydrophobic transmembrane domain; the second form corresponds to a soluble protein constituted by the first 165 aa of the extracellular domain released by a posttranslational processing, consisting in a proteolytic cleavage of the mature SCF in the extracellular juxtamembrane region. The full length transcripts encode for a transmembrane precursor of the soluble protein; an alternative splicing that involves the region corresponding to exon 6 of the SCF cDNA, which contains the proteolytic cleavage site, encodes for a surface molecule. Jiang et al. evidenced the crystallized structure of interaction between SCF and c-KIT and revealed the common structure of a bundle of 4 α-helices linked by two intra-molecular disulfide bridges.
Expression According to description of Bedell et al., the SCF encoding mRNA is characterized by a short 5' untranslated region, a 0.8 kb open reading frame, and by a long 3' untranslated region. In the 5' region, there are three ATG motifs where the last is used as the initiation site. A TATA box consensus sequence (TATAAA) and three overlapping GGCGGG motifs are located at twenty-eight bases upstream of the transcription initiation sites. These are binding sites for the transcription factors TFIID and SP1, respectively. Kobi et al. reported that the POU-homeodomain transcription factor POU3F2, expressed in neurons and in melanoma cells, regulates the SCF promoter through a cluster of four closely spaced binding sites located in the proximal promoter. It should be noted that UVB light is also known to induce expression of SCF in human epidermal cells both on the mRNA level and is soluble as well as membrane-bound SCF, but the mechanism of induction of SCF gene expression by UVB is still unknown. It has been also reported that HIF-1 upregulates the expression of SCF in response to hypoxia as well as to growth factor receptor activation. In Sertoli cells, SCF expression is up-regulated by treatment with follicle stimulating hormone (FSH) through an increasing of cAMP level.
SCF transcripts have been found in the cells surrounding kit-positive cells, such as granulosa and Sertoli cells, bone marrow stromal cells and in fibroblasts, keratinocytes and mature granulocytes; SCF expression of peripheral lymphocytes and monocytes is still controversial.
Localisation Plasma membrane or interstitial space. It is interesting to note that Faber et al. showed that disintegrin and metalloproteinase ADAM10 has an important role in mast cell migration and distribution.
In fact, they evidenced that ADAM 10, expressed at high levels by mast cells, is required for SCF-mediated mast cell migration.
Function SCF/MGF binding of receptor KIT, with tyrosine kinase activity, induces receptor dimerization, autophosphorylation and signal transduction via molecules containing SH2-domains; the soluble and the transmembrane protein have a different biological activity; the soluble form mainly stimulates cellular proliferation; the membrane-bound isoform induces an activation of the receptor more prolonged than the soluble one.
Homology With PDGFRb, PDGFRa, and CSF-1.

Mutations

Germinal Human mutations are yet unknown in human MGF/SCF gene; mouse mutations at the murine steel (Sl) locus that encodes MGF are known and give rise to deficiencies in pigment cells, germ cells, and blood cells; in particular the steel-Dickie (Sld) mouse has a 4.0-kb intragenic deletion that truncates the Sl coding sequence; Sld mice are only capable of encoding a soluble truncated growth factor that lacks both transmembrane and cytoplasmic domains.

Implicated in

Entity Mastocytosis
Note In skin from patients with mastocytosis, MGF was found prevalently free in the dermis and in extracellular spaces between keratinocytes suggesting the presence of a soluble form of the protein; altered distribution of mast cell growth factor in the skin of patients with cutaneous mastocytosis is consistent with abnormal production of the soluble form of the factor, resulting by an increased cleavage of SCF with excessive release of a soluble form from the normally membrane bound form; no sequence abnormalities were detected in MGF mRNA.
Janson et al. evidenced that RIN3, a RAS effector, is highly enriched in mast cells, and that is involved in a complex with BIN2, a membrane binding protein implicated in endocytosis. They also demonstrated that RIN3 negatively regulates KIT internalization process and also that KIT down-regulation is enhanced by RIN3 activity.
  
Entity Gynecological tumors
Note Findings obtained on three cervical carcinomas (ovarian serous adenocarcinoma, small cell carcinoma and ovarian immature teratoma) and two gynecological cancer cell lines (ME180 and HGCM) demonstrate coexpression of c-Kit receptor and SCF; these observations are consistent with the possibility that an autocrine activation of SCF/KIT system might be involved in gynecological malignancies.
  
Entity Small cell lung cancer
Note SCF is expressed in small cell lung cancer (SCLC); abundant expression of SCF and c-Kit mRNA was seen in 32% of SCLC cell lines and 66% of SCLC tumors; an autocrine mechanism in the pathogenesis of SCLC is strongly suggested.
  
Entity Prostate cancer
Note Recently, Wiesner et al. suggested that SCF release from prostate cancer (PC) cells to the extracellular milieu has a potential contribution to prostate cancer bone metastasis.
  
Entity Pancreatic cancer
Note c-KIT expression and SCF/c-KIT interaction are strictly linked to invasion and proliferation of pancreatic cancer cells. Zhang et al. recently showed the SCF/c-KIT signaling promotes the invasion of pancreatic cells, via HIF-1α in normoxic condition and through PI3K/AKT and RAS/MEK/ERK pathways.
  

External links

Nomenclature
HGNC (Hugo)KITLG   6343
Cards
AtlasMGFID142
Entrez_Gene (NCBI)KITLG  4254  KIT ligand
GeneCards (Weizmann)KITLG
Ensembl (Hinxton) [Gene_View]  chr12:88886570-88974250 [Contig_View]  KITLG [Vega]
AceView (NCBI)KITLG
Genatlas (Paris)KITLG
WikiGenes4254
SOURCE (Princeton)NM_000899 NM_003994
Genomic and cartography
GoldenPath (UCSC)KITLG  -  12q21.32   chr12:88886570-88974250 -  12q22   [Description]    (hg19-Feb_2009)
EnsemblKITLG - 12q22 [CytoView]
Mapping of homologs : NCBIKITLG [Mapview]
OMIM145250   184745   611664   
Gene and transcription
Genbank (Entrez)AF119835 AF400436 AF400437 AK025245 AK055903
RefSeq transcript (Entrez)NM_000899 NM_003994
RefSeq genomic (Entrez)AC_000144 NC_000012 NC_018923 NG_012098 NT_029419 NW_001838061 NW_004929384
Consensus coding sequences : CCDS (NCBI)KITLG
Cluster EST : UnigeneHs.1048 [ NCBI ]
CGAP (NCI)Hs.1048
Alternative Splicing : Fast-db (Paris)GSHG0007665
Gene ExpressionKITLG [ NCBI-GEO ]     KITLG [ SEEK ]   KITLG [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP21583 (Uniprot)
NextProtP21583  [Medical]
With graphics : InterProP21583
Splice isoforms : SwissVarP21583 (Swissvar)
Domains : Interpro (EBI)4_helix_cytokine-like_core    4_helix_cytokine_core    SCF   
Related proteins : CluSTrP21583
Domain families : Pfam (Sanger)SCF (PF02404)   
Domain families : Pfam (NCBI)pfam02404   
DMDM Disease mutations4254
Blocks (Seattle)P21583
PDB (SRS)1EXZ    1SCF    2E9W   
PDB (PDBSum)1EXZ    1SCF    2E9W   
PDB (IMB)1EXZ    1SCF    2E9W   
PDB (RSDB)1EXZ    1SCF    2E9W   
Peptide AtlasP21583
HPRD01698
IPIIPI00009450   IPI00220142   IPI00479376   IPI01010816   
Protein Interaction databases
DIP (DOE-UCLA)P21583
IntAct (EBI)P21583
BioGRIDKITLG
IntegromeDBKITLG
STRING (EMBL)KITLG
Ontologies - Pathways
QuickGOP21583
Ontology : AmiGOneural crest cell migration  positive regulation of myeloid leukocyte differentiation  cytokine activity  stem cell factor receptor binding  protein binding  extracellular region  extracellular space  cytoplasm  cytoskeleton  plasma membrane  plasma membrane  cell adhesion  signal transduction  epidermal growth factor receptor signaling pathway  growth factor activity  cell proliferation  fibroblast growth factor receptor signaling pathway  male gonad development  integral component of membrane  negative regulation of mast cell apoptotic process  embryonic hemopoiesis  ectopic germ cell programmed cell death  Fc-epsilon receptor signaling pathway  positive regulation of MAP kinase activity  innate immune response  positive regulation of melanocyte differentiation  positive regulation of DNA replication  positive regulation of Ras protein signal transduction  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  positive regulation of peptidyl-tyrosine phosphorylation  positive regulation of mast cell proliferation  extrinsic apoptotic signaling pathway in absence of ligand  
Ontology : EGO-EBIneural crest cell migration  positive regulation of myeloid leukocyte differentiation  cytokine activity  stem cell factor receptor binding  protein binding  extracellular region  extracellular space  cytoplasm  cytoskeleton  plasma membrane  plasma membrane  cell adhesion  signal transduction  epidermal growth factor receptor signaling pathway  growth factor activity  cell proliferation  fibroblast growth factor receptor signaling pathway  male gonad development  integral component of membrane  negative regulation of mast cell apoptotic process  embryonic hemopoiesis  ectopic germ cell programmed cell death  Fc-epsilon receptor signaling pathway  positive regulation of MAP kinase activity  innate immune response  positive regulation of melanocyte differentiation  positive regulation of DNA replication  positive regulation of Ras protein signal transduction  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  positive regulation of peptidyl-tyrosine phosphorylation  positive regulation of mast cell proliferation  extrinsic apoptotic signaling pathway in absence of ligand  
Pathways : BIOCARTAErythrocyte Differentiation Pathway [Genes]    Regulation of BAD phosphorylation [Genes]    IL 17 Signaling Pathway [Genes]    Melanocyte Development and Pigmentation [Genes]    CDK Regulation of DNA Replication [Genes]   
Pathways : KEGGRas signaling pathway    Rap1 signaling pathway    Cytokine-cytokine receptor interaction    PI3K-Akt signaling pathway    Hematopoietic cell lineage    Melanogenesis    Pathways in cancer   
REACTOMEP21583 [protein]
REACTOME PathwaysREACT_116125 Disease [pathway]
REACTOME PathwaysREACT_6900 Immune System [pathway]
REACTOME PathwaysREACT_111102 Signal Transduction [pathway]
Protein Interaction DatabaseKITLG
Wikipedia pathwaysKITLG
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)KITLG
SNP (GeneSNP Utah)KITLG
SNP : HGBaseKITLG
Genetic variants : HAPMAPKITLG
1000_GenomesKITLG 
CONAN: Copy Number AnalysisKITLG 
Somatic Mutations in Cancer : COSMICKITLG 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DECIPHER (Syndromes)12:88886570-88974250
Mutations and Diseases : HGMDKITLG
OMIM145250    184745    611664   
MedgenKITLG
GENETestsKITLG
Disease Genetic AssociationKITLG
Huge Navigator KITLG [HugePedia]  KITLG [HugeCancerGEM]
Genomic VariantsKITLG  KITLG [DGVbeta]
Exome VariantKITLG
dbVarKITLG
ClinVarKITLG
snp3D : Map Gene to Disease4254
DGIdb (Curated mutations)KITLG
DGIdb (Drug Gene Interaction db)KITLG
General knowledge
Homologs : HomoloGeneKITLG
Homology/Alignments : Family Browser (UCSC)KITLG
Phylogenetic Trees/Animal Genes : TreeFamKITLG
Chemical/Protein Interactions : CTD4254
Chemical/Pharm GKB GenePA30129
Clinical trialKITLG
Other databases
Probes
Litterature
PubMed177 Pubmed reference(s) in Entrez
CoreMineKITLG
GoPubMedKITLG
iHOPKITLG

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Contributor(s)

Written10-1998Alessandro Beghini
Department of Biology and Genetics, Medical Faculty, University of Milan, Italy
Updated06-2000Lidia Larizza, Alessandro Beghini
Department of Biology and Genetics, Medical Faculty, University of Milan, Italy
Updated08-2014Alessandro Beghini, Francesca Lazzaroni
Department of Biology and Genetics, Medical Faculty, University of Milan, Italy

Citation

This paper should be referenced as such :
Beghini A, Lazzaroni F
KITLG (KIT ligand);
Atlas Genet Cytogenet Oncol Haematol. August 2014
Free online version   Free pdf version   [Bibliographic record ]
Atlas Genet Cytogenet Oncol Haematol. August 2014
Atlas Genet Cytogenet Oncol Haematol. August 2014
URL : http://AtlasGeneticsOncology.org/Genes/MGFID142.html

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indexed on : Thu Dec 4 15:43:01 CET 2014

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