Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

KITLG (KIT ligand)

Written1998-10Alessandro Beghini
Department of Biology, Genetics, Medical Faculty, University of Milan, Italy
Updated2000-06Lidia Larizza, Alessandro Beghini
Department of Biology, Genetics, Medical Faculty, University of Milan, Italy
Updated2014-08Alessandro Beghini, Francesca Lazzaroni
Department of Biology, Genetics, Medical Faculty, University of Milan, Italy

Abstract Review on KITLG (KIT ligand), with data on DNA, on the protein encoded, and where the gene is implicated.

(Note : for Links provided by Atlas : click)


Other aliasMGF
LocusID (NCBI) 4254
Atlas_Id 142
Location 12q21.32  [Link to chromosome band 12q21]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
KITLG (12q21.32) / CCDC6 (10q21.2)KITLG (12q21.32) / ODC1 (2p25.1)KITLG (12q21.32) / TNNC1 (3p21.1)


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 (


  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.


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.


The biology of stem cell factor and its receptor C-kit.
Ashman LK.
Int J Biochem Cell Biol. 1999 Oct;31(10):1037-51. (REVIEW)
PMID 10582338
UVB irradiation increases the release of SCF from human epidermal cells.
Baba H, Uchiwa H, Watanabe S.
J Invest Dermatol. 2005 May;124(5):1075-7.
PMID 15854051
DNA rearrangements located over 100 kb 5' of the Steel (Sl)-coding region in Steel-panda and Steel-contrasted mice deregulate Sl expression and cause female sterility by disrupting ovarian follicle development.
Bedell MA, Brannan CI, Evans EP, Copeland NG, Jenkins NA, Donovan PJ.
Genes Dev. 1995 Feb 15;9(4):455-70.
PMID 7533739
Multiple pathways for Steel regulation suggested by genomic and sequence analysis of the murine Steel gene.
Bedell MA, Copeland NG, Jenkins NA.
Genetics. 1996 Mar;142(3):927-34.
PMID 8849898
SCF and G-CSF lead to the synergistic induction of proliferation and gene expression through complementary signaling pathways.
Duarte RF, Frank DA.
Blood. 2000 Nov 15;96(10):3422-30.
PMID 11071637
ADAM10 is required for SCF-induced mast cell migration.
Faber TW, Pullen NA, Fernando JF, Kolawole EM, McLeod JJ, Taruselli M, Williams KL, Rivera KO, Barnstein BO, Conrad DH, Ryan JJ.
Cell Immunol. 2014 Jul;290(1):80-8. doi: 10.1016/j.cellimm.2014.05.005. Epub 2014 May 21.
PMID 24950026
Expression of interleukins 1, 3, 6, stem cell factor and their receptors in acute leukemia blast cells and in normal peripheral lymphocytes and monocytes.
Ferrari S, Grande A, Manfredini R, Tagliafico E, Zucchini P, Torelli G, Torelli U.
Eur J Haematol. 1993 Mar;50(3):141-8.
PMID 7682516
Targeting receptor tyrosine kinase signalling in small cell lung cancer (SCLC): what have we learned so far?
Fischer B, Marinov M, Arcaro A.
Cancer Treat Rev. 2007 Jun;33(4):391-406. Epub 2007 Mar 26. (REVIEW)
PMID 17368733
Bin2, a functionally nonredundant member of the BAR adaptor gene family.
Ge K, Prendergast GC.
Genomics. 2000 Jul 15;67(2):210-20.
PMID 10903846
Hypoxia-inducible factor (HIF)-1 alpha directly enhances the transcriptional activity of stem cell factor (SCF) in response to hypoxia and epidermal growth factor (EGF).
Han ZB, Ren H, Zhao H, Chi Y, Chen K, Zhou B, Liu YJ, Zhang L, Xu B, Liu B, Yang R, Han ZC.
Carcinogenesis. 2008 Oct;29(10):1853-61. doi: 10.1093/carcin/bgn066. Epub 2008 Mar 13.
PMID 18339685
Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand.
Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, Crystal RG, Besmer P, Lyden D, Moore MA, Werb Z, Rafii S.
Cell. 2002 May 31;109(5):625-37.
PMID 12062105
The majority of stem cell factor exists as monomer under physiological conditions. Implications for dimerization mediating biological activity.
Hsu YR, Wu GM, Mendiaz EA, Syed R, Wypych J, Toso R, Mann MB, Boone TC, Narhi LO, Lu HS, Langley KE.
J Biol Chem. 1997 Mar 7;272(10):6406-15.
PMID 9045664
Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2.
Huang EJ, Nocka KH, Buck J, Besmer P.
Mol Biol Cell. 1992 Mar;3(3):349-62.
PMID 1378327
Coexpression of the c-kit receptor and the stem cell factor in gynecological tumors.
Inoue M, Kyo S, Fujita M, Enomoto T, Kondoh G.
Cancer Res. 1994 Jun 1;54(11):3049-53.
PMID 7514496
RIN3 is a negative regulator of mast cell responses to SCF.
Janson C, Kasahara N, Prendergast GC, Colicelli J.
PLoS One. 2012;7(11):e49615. doi: 10.1371/journal.pone.0049615. Epub 2012 Nov 20.
PMID 23185384
Receptor signaling: when dimerization is not enough.
Jiang G, Hunter T.
Curr Biol. 1999 Jul 29-Aug 12;9(15):R568-71. (REVIEW)
PMID 10469554
Structure of the active core of human stem cell factor and analysis of binding to its receptor kit.
Jiang X, Gurel O, Mendiaz EA, Stearns GW, Clogston CL, Lu HS, Osslund TD, Syed RS, Langley KE, Hendrickson WA.
EMBO J. 2000 Jul 3;19(13):3192-203.
PMID 10880433
RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway.
Kajiho H, Saito K, Tsujita K, Kontani K, Araki Y, Kurosu H, Katada T.
J Cell Sci. 2003 Oct 15;116(Pt 20):4159-68.
PMID 12972505
Genome-wide analysis of POU3F2/BRN2 promoter occupancy in human melanoma cells reveals Kitl as a novel regulated target gene.
Kobi D, Steunou AL, Dembele D, Legras S, Larue L, Nieto L, Davidson I.
Pigment Cell Melanoma Res. 2010 Jun;23(3):404-18. doi: 10.1111/j.1755-148X.2010.00697.x. Epub 2010 Mar 17.
PMID 20337985
Substrate hydrolysis by matrix metalloproteinase-9.
Kridel SJ, Chen E, Kotra LP, Howard EW, Mobashery S, Smith JW.
J Biol Chem. 2001 Jun 8;276(23):20572-8. Epub 2001 Mar 14.
PMID 11279151
Kit receptor dimerization is driven by bivalent binding of stem cell factor.
Lemmon MA, Pinchasi D, Zhou M, Lax I, Schlessinger J.
J Biol Chem. 1997 Mar 7;272(10):6311-7.
PMID 9045650
Stem cell factor receptor/c-Kit: from basic science to clinical implications.
Lennartsson J, Ronnstrand L.
Physiol Rev. 2012 Oct;92(4):1619-49. doi: 10.1152/physrev.00046.2011. (REVIEW)
PMID 23073628
Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis.
Longley BJ Jr, Morganroth GS, Tyrrell L, Ding TG, Anderson DM, Williams DE, Halaban R.
N Engl J Med. 1993 May 6;328(18):1302-7.
PMID 7682288
Chymase cleavage of stem cell factor yields a bioactive, soluble product.
Longley BJ, Tyrrell L, Ma Y, Williams DA, Halaban R, Langley K, Lu HS, Schechter NM.
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9017-21.
PMID 9256427
Primary structure and functional expression of rat and human stem cell factor DNAs.
Martin FH, Suggs SV, Langley KE, Lu HS, Ting J, Okino KH, Morris CF, McNiece IK, Jacobsen FW, Mendiaz EA, et al.
Cell. 1990 Oct 5;63(1):203-11.
PMID 2208279
Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells.
Pedersen M, Lofstedt T, Sun J, Holmquist-Mengelbier L, Pahlman S, Ronnstrand L.
Biochem Biophys Res Commun. 2008 Dec 5;377(1):98-103. doi: 10.1016/j.bbrc.2008.09.102. Epub 2008 Oct 1.
PMID 18834862
Human peripheral blood granulocytes and myeloid leukemic cell lines express both transcripts encoding for stem cell factor.
Ramenghi U, Ruggieri L, Dianzani I, Rosso C, Brizzi MF, Camaschella C, Pietsch T, Saglio G.
Stem Cells. 1994 Sep;12(5):521-6.
PMID 7528592
Stem cell factor and its receptor c-Kit as targets for inflammatory diseases.
Reber L, Da Silva CA, Frossard N.
Eur J Pharmacol. 2006 Mar 8;533(1-3):327-40. Epub 2006 Feb 17. (REVIEW)
PMID 16483568
Expression of c-kit and kit-ligand in benign and malignant prostatic tissues.
Simak R, Capodieci P, Cohen DW, Fair WR, Scher H, Melamed J, Drobnjak M, Heston WD, Stix U, Steiner G, Cordon-Cardo C.
Histol Histopathol. 2000 Apr;15(2):365-74.
PMID 10809354
C-kit and its ligand stem cell factor: potential contribution to prostate cancer bone metastasis.
Wiesner C, Nabha SM, Dos Santos EB, Yamamoto H, Meng H, Melchior SW, Bittinger F, Thuroff JW, Vessella RL, Cher ML, Bonfil RD.
Neoplasia. 2008 Sep;10(9):996-1003.
PMID 18714401
Stem cell factor/c-kit signaling enhances invasion of pancreatic cancer cells via HIF-1a under normoxic condition.
Zhang M, Ma Q, Hu H, Zhang D, Li J, Ma G, Bhat K, Wu E.
Cancer Lett. 2011 Apr 28;303(2):108-17. doi: 10.1016/j.canlet.2011.01.017. Epub 2011 Feb 12.
PMID 21320746
Human mast cells express stem cell factor.
Zhang S, Anderson DF, Bradding P, Coward WR, Baddeley SM, MacLeod JD, McGill JI, Church MK, Holgate ST, Roche WR.
J Pathol. 1998 Sep;186(1):59-66.
PMID 9875141
Crystal structure of human stem cell factor: implication for stem cell factor receptor dimerization and activation.
Zhang Z, Zhang R, Joachimiak A, Schlessinger J, Kong XP.
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7732-7.
PMID 10884405
Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor.
Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, Hsu RY, Birkett NC, Okino KH, Murdock DC, et al.
Cell. 1990 Oct 5;63(1):213-24.
PMID 1698556


This paper should be referenced as such :
Alessandro Beghini, Francesca Lazzaroni
KITLG (KIT ligand)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(5):333-336.
Free journal version : [ pdf ]   [ DOI ]
On line version :
History of this paper:
Beghini, A. KITLG (KIT ligand). Atlas Genet Cytogenet Oncol Haematol. 1999;3(1):6-7.
Larizza, L ; Beghini, A. KITLG (KIT ligand). Atlas Genet Cytogenet Oncol Haematol. 2000;4(3):99-100.

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 3 ]
  Systemic mast cell disease (SMCD)
Juvenile Chronic Myelogenous Leukemia (JCML)
Systemic mast cell disease (SMCD)

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  t(3;12)(p21;q21) KITLG/TNNC1
t(10;12)(q21;q21) KITLG/CCDC6

Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)4254
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Oct 18 17:42:48 CEST 2018

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us