KITLG (KIT ligand)

2014-08-01   Alessandro Beghini , Francesca Lazzaroni 

Department of Biology, Genetics, Medical Faculty, University of Milan, Italy




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


Atlas Image


KITLG/SCF is encoded by 10 exons (transcript variant b) and 9 exons (transcript variant a).


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 (


Atlas Image
Adapted from Johan Lennartsson and Lars Rönnstrand, 2012.


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.


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.


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.


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.


With PDGFRb, PDGFRa, and CSF-1.



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 name
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 name
Gynecological tumors
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 name
Small cell lung cancer
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 name
Prostate cancer
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 name
Pancreatic cancer
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.


Pubmed IDLast YearTitleAuthors
105823381999The biology of stem cell factor and its receptor C-kit.Ashman LK et al
158540512005UVB irradiation increases the release of SCF from human epidermal cells.Baba H et al
75337391995DNA 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 et al
88498981996Multiple pathways for Steel regulation suggested by genomic and sequence analysis of the murine Steel gene.Bedell MA et al
110716372000SCF and G-CSF lead to the synergistic induction of proliferation and gene expression through complementary signaling pathways.Duarte RF et al
249500262014ADAM10 is required for SCF-induced mast cell migration.Faber TW et al
76825161993Expression 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 et al
173687332007Targeting receptor tyrosine kinase signalling in small cell lung cancer (SCLC): what have we learned so far?Fischer B et al
109038462000Bin2, a functionally nonredundant member of the BAR adaptor gene family.Ge K et al
183396852008Hypoxia-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 et al
120621052002Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand.Heissig B et al
90456641997The majority of stem cell factor exists as monomer under physiological conditions. Implications for dimerization mediating biological activity.Hsu YR et al
13783271992Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2.Huang EJ et al
75144961994Coexpression of the c-kit receptor and the stem cell factor in gynecological tumors.Inoue M et al
231853842012RIN3 is a negative regulator of mast cell responses to SCF.Janson C et al
104695541999Receptor signaling: when dimerization is not enough.Jiang G et al
108804332000Structure of the active core of human stem cell factor and analysis of binding to its receptor kit.Jiang X et al
129725052003RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway.Kajiho H et al
203379852010Genome-wide analysis of POU3F2/BRN2 promoter occupancy in human melanoma cells reveals Kitl as a novel regulated target gene.Kobi D et al
112791512001Substrate hydrolysis by matrix metalloproteinase-9.Kridel SJ et al
90456501997Kit receptor dimerization is driven by bivalent binding of stem cell factor.Lemmon MA et al
230736282012Stem cell factor receptor/c-Kit: from basic science to clinical implications.Lennartsson J et al
76822881993Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis.Longley BJ Jr et al
92564271997Chymase cleavage of stem cell factor yields a bioactive, soluble product.Longley BJ et al
22082791990Primary structure and functional expression of rat and human stem cell factor DNAs.Martin FH et al
188348622008Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells.Pedersen M et al
75285921994Human peripheral blood granulocytes and myeloid leukemic cell lines express both transcripts encoding for stem cell factor.Ramenghi U et al
164835682006Stem cell factor and its receptor c-Kit as targets for inflammatory diseases.Reber L et al
108093542000Expression of c-kit and kit-ligand in benign and malignant prostatic tissues.Simak R et al
187144012008C-kit and its ligand stem cell factor: potential contribution to prostate cancer bone metastasis.Wiesner C et al
213207462011Stem cell factor/c-kit signaling enhances invasion of pancreatic cancer cells via HIF-1α under normoxic condition.Zhang M et al
98751411998Human mast cells express stem cell factor.Zhang S et al
108844052000Crystal structure of human stem cell factor: implication for stem cell factor receptor dimerization and activation.Zhang Z et al
16985561990Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor.Zsebo KM et al

Other Information

Locus ID:

NCBI: 4254
MIM: 184745
HGNC: 6343
Ensembl: ENSG00000049130


dbSNP: 4254
ClinVar: 4254
TCGA: ENSG00000049130


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Hematopoietic cell lineageKEGGko04640
Cytokine-cytokine receptor interactionKEGGhsa04060
Hematopoietic cell lineageKEGGhsa04640
Pathways in cancerKEGGhsa05200
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
Regulation of KIT signalingREACTOMER-HSA-1433559
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
RET signalingREACTOMER-HSA-8853659

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
166163342006Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain.353
180831062007cis-Regulatory changes in Kit ligand expression and parallel evolution of pigmentation in sticklebacks and humans.137
194836822009Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer.132
194836822009Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer.132
194836812009A genome-wide association study of testicular germ cell tumor.123
155261602004Signal transduction via the stem cell factor receptor/c-Kit.103
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
287149702017Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF.74
149853552004Stem cell factor/c-kit signaling promotes the survival, migration, and capillary tube formation of human umbilical vein endothelial cells.66
175565982007Differentiation of human embryonic stem cells in serum-free medium reveals distinct roles for bone morphogenetic protein 4, vascular endothelial growth factor, stem cell factor, and fibroblast growth factor 2 in hematopoiesis.58


Alessandro Beghini ; Francesca Lazzaroni

KITLG (KIT ligand)

Atlas Genet Cytogenet Oncol Haematol. 2014-08-01

Online version:

Historical Card

2000-06-01 KITLG (KIT ligand) by  Lidia Larizza,Alessandro Beghini 

Department of Biology, Genetics, Medical Faculty, University of Milan, Italy

1998-10-01 KITLG (KIT ligand) by  Alessandro Beghini 

Department of Biology, Genetics, Medical Faculty, University of Milan, Italy