Affinage

KITLG

Kit ligand · UniProt P21583

Round 2 corrected
Length
273 aa
Mass
30.9 kDa
Annotated
2026-04-28
130 papers in source corpus 27 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KITLG (Kit ligand/stem cell factor) is a transmembrane growth factor that signals through the receptor tyrosine kinase KIT to regulate survival, proliferation, migration, and differentiation of hematopoietic stem cells, melanocytes, germ cells, mast cells, and endothelial cells (PMID:2208279, PMID:11861309, PMID:28714970). It is produced as two alternatively spliced transmembrane isoforms (KL-1 and KL-2) that differ in susceptibility to regulated proteolytic shedding, with tissue-specific isoform ratios controlling the balance of membrane-bound versus soluble ligand (PMID:1378327); efficient surface delivery requires a C-terminal valine-dependent ER export signal in its cytoplasmic tail (PMID:15475566). Binding of KITLG induces KIT receptor dimerization via lateral D4–D4 and D5–D5 domain contacts, activating downstream PI3K/Akt, ERK/MAPK, STAT5/6, and GSK-3β/β-catenin cascades through adaptors including Gab2 and Gαi1/3 (PMID:17662946, PMID:11861309, PMID:15217825, PMID:31434494, PMID:37063428). Cis-regulatory variation at the KITLG locus—including a LEF1-responsive enhancer harboring the SNP rs12821256—underlies natural pigmentation differences across vertebrates, and coding mutations in KITLG cause familial progressive hyper- and hypopigmentation (PMID:24880339, PMID:18083106, PMID:21368769).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1990 High

    Cloning of KITLG established it as a hematopoietic growth factor that synergizes with colony-stimulating factors to expand myeloid and lymphoid progenitors, defining its primary biological role.

    Evidence cDNA cloning from rat and human with recombinant protein expression and bone marrow progenitor proliferation assays

    PMID:2208279

    Open questions at the time
    • receptor identity (KIT) known but structural basis of interaction unresolved
    • in vivo requirement not yet demonstrated by genetic loss-of-function of KITLG itself
  2. 1992 High

    Discovery of two alternatively spliced KITLG isoforms (KL-1/KL-2) with differential proteolytic shedding efficiency revealed that the balance of membrane-bound versus soluble ligand is regulated at the level of splicing and cell-surface cleavage.

    Evidence Alternative splicing analysis, phorbol ester and calcium ionophore stimulation, Western blot of shed products

    PMID:1378327

    Open questions at the time
    • identity of the protease(s) responsible for constitutive and regulated shedding not determined
    • functional consequence of membrane-bound vs soluble forms on KIT signaling duration not dissected
  3. 1997 Medium

    Identification of PI3K p110δ and p110α recruitment to KIT-associated complexes after SCF stimulation placed PI3K activation as a proximal signaling event downstream of KITLG/KIT.

    Evidence Immunoprecipitation and in vitro kinase assays in leukocytes stimulated with SCF

    PMID:9113989

    Open questions at the time
    • relative functional contributions of p110α vs p110δ downstream of KIT not determined
    • recruitment mechanism (direct vs adaptor-mediated) not fully resolved
  4. 2002 High

    Gab2 was identified as a required adaptor downstream of KIT, linking KITLG signaling to ERK and PI3K/Akt activation and mast cell development, thereby defining the signal transduction architecture from receptor to effector kinases.

    Evidence Gab2 knockout mice with impaired mast cell development and reduced ERK/Akt activation upon SCF stimulation

    PMID:11861309

    Open questions at the time
    • whether Gab2 is required in non-mast cell lineages (e.g. melanocytes, HSCs) for KITLG signaling not tested
    • structural basis of Gab2–KIT interaction not resolved
  5. 2002 Medium

    An ENU-induced allelic series of Kitl mutations mapped functional requirements to conserved α-helical domains, establishing structure–function relationships in vivo.

    Evidence ENU mutagenesis screen with sequencing and structural mapping of seven point mutations

    PMID:12242244

    Open questions at the time
    • no crystal structure of KITLG alone or in complex at this point to place mutations structurally
    • allele severity not quantitatively correlated with receptor binding affinity
  6. 2004 High

    Identification of a C-terminal valine as an ER export signal for KITLG revealed that its surface delivery depends on COPII-mediated vesicular transport, establishing a trafficking control point upstream of ligand presentation.

    Evidence Mutagenesis of cytoplasmic tail valine, live-cell GFP imaging, ER accumulation phenotype

    PMID:15475566

    Open questions at the time
    • COPII coat subunit specificity for KITLG recognition not identified
    • whether this export signal is regulated in physiological contexts unknown
  7. 2004 High

    Demonstration that SCF/KIT activates PI3K/Akt and ERK in endothelial cells to drive survival, migration, and tube formation extended the biological scope of KITLG signaling beyond hematopoietic lineages to angiogenesis.

    Evidence Pharmacological inhibition (PI3K, MEK, c-Kit) combined with HUVEC survival, migration, and tube formation assays

    PMID:14985355

    Open questions at the time
    • relative importance of soluble vs membrane-bound KITLG for angiogenesis not addressed
    • in vivo confirmation of endothelial-autonomous KIT requirement pending
  8. 2004 High

    SCF/KIT uniquely activates STAT5 and STAT6 in mast cells (distinct from FcεRI), revealing receptor-specific signaling that explains the non-redundant role of KITLG in mast cell biology.

    Evidence Phospho-specific Western blotting in primary human mast cells comparing SCF vs antigen stimulation

    PMID:15217825

    Open questions at the time
    • direct transcriptional targets of STAT5/6 downstream of KIT in mast cells not catalogued
    • mechanism of synergy between SCF and antigen for degranulation not molecularly defined
  9. 2005 Medium

    Graded Kitl hypomorphic alleles in mice showed that different threshold levels of KITLG are required for PGC proliferation versus migration, demonstrating quantitative dose-dependence of KITLG in germ cell development.

    Evidence Phenotypic comparison of ENU-induced Kitl allelic series at multiple developmental stages

    PMID:15917341

    Open questions at the time
    • downstream pathways mediating proliferation vs migration distinction not identified
    • whether membrane-bound vs soluble KITLG accounts for the threshold difference untested
  10. 2007 High

    Crystal structures of the full KIT ectodomain in complex with SCF resolved the activation mechanism: SCF induces KIT dimerization, which enables homotypic D4–D4 and D5–D5 lateral contacts essential for kinase activation, explaining how oncogenic mutations in these interfaces constitutively activate KIT.

    Evidence X-ray crystallography of KIT ectodomain ± SCF, point mutagenesis of D4–D4 contacts with cell-based KIT activation assays

    PMID:17662946

    Open questions at the time
    • full-length KIT structural model including kinase domain not available
    • dynamics of dimer rearrangement at the membrane not captured by crystal structure
  11. 2007 High

    Cis-regulatory changes at the KITLG locus were shown to drive parallel evolution of reduced pigmentation in sticklebacks and to contribute to human skin color, establishing KITLG as a major evolutionary pigmentation gene controlled at the transcriptional level.

    Evidence Genetic crosses and expression studies in sticklebacks combined with admixture mapping in humans

    PMID:18083106

    Open questions at the time
    • specific transcription factors and enhancer elements not yet identified
    • quantitative effect size in human pigmentation not precisely measured
  12. 2011 High

    TAK1 was placed upstream of KITLG expression in keratinocytes, linking innate signaling kinases to SCF/c-Kit/Akt-mediated protection against ROS-induced apoptosis and defining a TAK1→KITLG→KIT→Akt survival axis in skin.

    Evidence TAK1 knockdown/overexpression, exogenous SCF rescue, pharmacological KIT/Akt inhibition, organotypic skin culture

    PMID:21233843

    Open questions at the time
    • mechanism by which TAK1 induces KITLG transcription not defined
    • whether this axis operates in non-keratinocyte contexts untested
  13. 2011 Medium

    Identification of KITLG coding mutations in familial progressive hyper- and hypopigmentation (FPHH) established KITLG as a Mendelian pigmentation disease gene and demonstrated that specific mutations impair membrane localization or soluble ligand secretion.

    Evidence Whole-exome sequencing with linkage analysis, in vitro membrane localization and secretion assays for identified mutations

    PMID:21368769 PMID:26522471

    Open questions at the time
    • dominant-negative vs haploinsufficiency mechanism for specific alleles not fully resolved
    • effect of mutations on KIT binding affinity not measured
  14. 2014 High

    A specific SNP (rs12821256) in a KITLG enhancer was shown to reduce LEF1-dependent transcription, and transgenic mice carrying the human variant had reduced hair pigmentation, providing the molecular basis for blond hair in Europeans.

    Evidence Enhancer reporter assays, LEF1 binding site mutagenesis, transgenic mouse enhancer knock-in

    PMID:24880339

    Open questions at the time
    • whether additional transcription factors cooperate with LEF1 at this enhancer unknown
    • melanocyte-specific vs keratinocyte-specific enhancer activity not fully dissected
  15. 2015 Medium

    KITLG was validated as a direct post-transcriptional target of miR-34c and miR-27a, establishing microRNA-mediated regulation of KITLG expression in colorectal cancer and melanocyte pigmentation contexts.

    Evidence Dual-luciferase 3′UTR reporter assays confirming direct miRNA binding, miRNA overexpression/inhibition with KITLG protein readouts

    PMID:26674205 PMID:31613171

    Open questions at the time
    • physiological relevance of miR-34c regulation of KITLG in normal colon epithelium not established
    • combinatorial effects of multiple KITLG-targeting miRNAs not assessed
  16. 2017 High

    Conditional deletion of Scf in bone marrow adipocytes demonstrated that adipocyte-derived KITLG is required for HSC maintenance and hematopoietic regeneration after myeloablation, identifying a niche-specific source of KITLG critical for emergency hematopoiesis.

    Evidence Adipoq-Cre/ER-driven conditional Scf knockout, irradiation and 5-FU models, HSC enumeration, survival analysis

    PMID:28714970

    Open questions at the time
    • whether adipocyte-derived KITLG acts via soluble or membrane-bound isoform in the niche not determined
    • relative contributions of adipocyte vs LepR+ stromal KITLG not quantitatively resolved
  17. 2019 High

    The SCF/KIT→GSK-3β→β-catenin signaling axis was identified as a driver of pathological neovascularization, and Gαi1/3 proteins were shown to be required co-transducers for KIT-mediated Akt-mTOR and ERK activation in endothelial cells, completing the proximal signaling chain from receptor to effectors.

    Evidence cKit mutant mice, anti-SCF antibody, β-catenin inhibitors in retinopathy models; Gαi1/3 CRISPR KO and co-immunoprecipitation with activated KIT in HUVECs

    PMID:31434494 PMID:37063428

    Open questions at the time
    • mechanism by which Gαi1/3 couples to a receptor tyrosine kinase (rather than GPCR) is structurally undefined
    • whether Gαi1/3 requirement extends to non-endothelial KITLG-responsive lineages is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the protease(s) responsible for constitutive and regulated KITLG ectodomain shedding, the structural basis for isoform-specific cleavage, and how membrane-bound versus soluble KITLG differentially activate KIT signaling duration and quality remain unresolved.
  • sheddase identity not definitively assigned despite candidates (ADAM17/ADAM10)
  • no quantitative model of how soluble vs membrane-bound SCF ratio tunes signal output in vivo
  • full-length KIT–SCF complex structure including transmembrane and kinase domains unavailable

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 7
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2
Partners
GAB2GNAI1GNAI3KITLEF1PIK3CD

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 KITLG (stem cell factor/SCF) was cloned from rat and human; truncated recombinant forms expressed in E. coli and mammalian cells retained biological activity, augmenting proliferation of myeloid and lymphoid hematopoietic progenitors in bone marrow cultures and showing synergy with colony-stimulating factors. cDNA cloning, recombinant protein expression, hematopoietic progenitor proliferation assays Cell High 2208279
1992 KITLG is produced as two transmembrane isoforms (KL-1 and KL-2) generated by alternative splicing. KL-1 is efficiently cleaved at the cell surface to produce soluble KL; KL-2 lacks the major proteolytic cleavage site (removed by splicing) and is shed with reduced efficiency. Phorbol ester and calcium ionophore induce cleavage of both isoforms at similar rates, indicating regulated shedding. The relative abundance of KL-1 vs KL-2 is controlled in a tissue-specific manner. Alternative splicing analysis, phorbol ester/calcium ionophore treatment, Western blot, cell surface cleavage assays Molecular biology of the cell High 1378327
2002 Gab2, an adaptor molecule with a pleckstrin homology domain, is required for KitL/c-Kit signaling and mast cell development. In Gab2-deficient mice, mast cell numbers were markedly reduced, and bone marrow-derived mast cells grew poorly in response to KitL. KitL-induced ERK MAP kinase and Akt activation were impaired in Gab2-deficient cells, placing Gab2 downstream of KitL/c-Kit and upstream of ERK and PI3K/Akt pathways. Gab2 knockout mouse, bone marrow-derived mast cell cultures, kinase activation assays (ERK, Akt Western blot) Blood High 11861309
2004 A C-terminal valine residue in the cytoplasmic tail of Kitl (positioned 19–36 amino acids from the transmembrane/cytoplasmic domain border) acts as a specific ER export signal. Deletion or substitution of this valine causes ER accumulation of Kitl and reduced cell surface transport. The valine-dependent motif recruits Kitl into COPII-coated ER exit sites for vesicular ER-to-Golgi transport. Mutagenesis, live-cell imaging with GFP fusion and ts-VSV-G reporter, subcellular fractionation, fluorescence microscopy The Journal of biological chemistry High 15475566
2004 SCF/c-Kit signaling promotes survival, migration, and capillary tube formation of human umbilical vein endothelial cells by rapidly activating Akt, Erk1/2, and c-Kit tyrosine phosphorylation. PI3K inhibitors (wortmannin, LY294002) and MEK inhibitor (PD98059) abrogated survival and tube formation, and c-Kit inhibitor STI-571 blocked these effects, demonstrating that the SCF/c-Kit → PI3K/Akt and Erk1/2 axes mediate endothelial cell survival and morphogenesis. Pharmacological inhibitors, c-Kit phosphorylation assays, cell survival/migration/tube formation assays The Journal of biological chemistry High 14985355
2004 c-Kit activation by SCF in mast cells uniquely activates STAT5 and STAT6 phosphorylation, while FcεRI uniquely activates PKC-dependent c-Jun/AP-1 induction. Both receptors converge on PI3K/Akt and MAPK. Kit ligand failed to induce degranulation alone but strongly synergized with antigen, and continuous KL exposure down-regulated signals that were reactivated by antigen co-stimulation. Phospho-specific Western blotting, cytokine transcript quantification, degranulation assays in human mast cells from CD34+ progenitors Blood High 15217825
2005 Analysis of an allelic series of hypomorphic KitlSl mutations in mice revealed that KITL requirements differ during PGC development: proliferation before and after migration requires different levels of KITL function, and different threshold levels of KITL support proliferation versus migration of primordial germ cells. ENU-induced hypomorphic allele series, genetic comparison of PGC numbers at developmental stages, histology Biology of reproduction Medium 15917341
2006 KIT is activated in all GISTs examined, even without KIT mutations. Both membrane-bound and soluble SCF mRNA isoforms are co-expressed in GIST cells and primary cultures, and SCF protein is detected within GIST cells, suggesting an autocrine/paracrine mechanism of KIT activation by KITLG. RT-PCR, ELISA, immunohistochemistry, Western blotting for phospho-KIT, primary GIST cell cultures British journal of cancer Medium 16570044
2007 Crystal structures of the entire KIT ectodomain before and after SCF stimulation showed that SCF binding drives KIT dimerization, with SCF's sole role being to bring two KIT molecules into proximity. Receptor dimerization induces conformational changes enabling lateral interactions between membrane-proximal Ig-like domains D4 and D5 of two KIT molecules. Point mutations in D4-D4 contact residues compromised KIT activation in cultured cells, and oncogenic mutations map to the D5-D5 interface. X-ray crystallography, site-directed mutagenesis, cell-based KIT activation assays Cell High 17662946
2007 cis-regulatory changes in the Kitlg gene underlie parallel evolution of reduced pigmentation in sticklebacks and contribute to human skin color variation. A divergent regulatory allele of Kitlg reduces expression in gill and skin tissue in freshwater sticklebacks, and admixture mapping confirmed the KITLG genomic region affects human skin color. The regulatory changes rather than coding changes drive pigmentation differences. Genetic crosses, high-resolution mapping, expression studies, admixture mapping in humans Cell High 18083106
2007 SCF (KITLG) overexpressed by neurons following brain injury and by glioma cells directly activates brain microvascular endothelial cells in vitro and induces angiogenesis in vivo. SCF downregulation inhibited tumor-mediated angiogenesis and glioma growth in vivo. In vitro endothelial cell activation assays, in vivo glioma xenograft models with SCF downregulation (shRNA), immunohistochemistry Cancer cell High 16616334
2008 VCD-induced ovarian follicle loss is associated with decreased Kit mRNA/protein and increased Kitl mRNA/protein expression. Addition of exogenous KITL to ovarian cultures during VCD exposure attenuated follicle loss, supporting that KIT/KITL signaling is critical for primordial and primary follicle survival and that VCD compromises this pathway. Microarray, RT-PCR, Western blot, in vitro ovarian culture with growth factor rescue experiments Biology of reproduction Medium 18448842
2009 SCF inhibits IGF-I-mediated proliferation of growth plate chondrocytes by attenuating ERK1/2 activation, and promotes chondrocyte differentiation in ATDC5 cells with distinct expression patterns for collagen X, collagen 2, aggrecan, and lysyl oxidase. Isolated bovine chondrocyte proliferation assays, ATDC5 differentiation assays, ERK1/2 phosphorylation Western blots Molecular endocrinology Medium 19897599
2011 TAK1 directly regulates SCF (KITLG) expression, which activates the PKBα (Akt) pro-survival pathway in keratinocytes to protect them from ROS-mediated apoptosis. TAK1 deficiency led to increased apoptosis and elevated ROS. Ectopic TAK1 expression or exogenous SCF restored this phenotype, and inhibition of SCF/c-Kit/PKBα pathway increased ROS and apoptosis in normal keratinocytes. TAK1 knockdown/overexpression, recombinant SCF rescue, pharmacological inhibitors of c-Kit/PKBα, FACS for ROS and apoptosis, organotypic skin culture Cell death and differentiation High 21233843
2011 KITLG mutations cause familial progressive hyper- and hypopigmentation (FPHH): three mutations identified in conserved β-strand of KITLG. In vitro studies showed the p.His67_Cys68delinsArg transmembrane isoform is undetectable at the cell membrane, while p.Leu104Val is membrane-located but reduces soluble KITLG secretion. These data suggest NS-UHL/AHL mutations cause loss-of-function, while the WS2 mutation may act via dominant-negative or gain-of-function through altered membrane incorporation and reduced secretion. Whole-exome sequencing, linkage analysis, in vitro cell membrane localization assays, secretion assays The Journal of investigative dermatology Medium 21368769 26522471
2014 A molecular basis for blond hair color in northern Europeans was identified: a regulatory enhancer within the KITLG locus contains the SNP rs12821256 that alters a LEF1 (lymphoid enhancer-binding factor 1) transcription factor binding site, reducing LEF1 responsiveness and enhancer activity in keratinocytes. Mice carrying the derived human KITLG enhancer variant show significantly reduced hair pigmentation, confirming that cis-regulatory reduction of KITLG expression drives the blond hair phenotype. Functional enhancer assays in keratinocytes, LEF1 binding site mutagenesis, transgenic mouse enhancer knock-in experiments Nature genetics High 24880339
2015 KITLG is a direct target of miR-34c in colorectal cancer cells. Resveratrol upregulates miR-34c (via promoter demethylation), which knocks down KITLG and suppresses CRC cell viability, proliferation, migration, invasion and promotes apoptosis. The effect was enhanced in p53-positive cells and likely involves PI3K/Akt pathway inactivation. In vivo, resveratrol elevated miR-34c and reduced KITLG in xenografts. Luciferase reporter assay (miR-34c targeting KITLG 3'UTR), lentiviral miR-34c overexpression/inhibition, MSP for methylation, xenograft models BMC cancer Medium 26674205
2015 KITLG mRNA is expressed as two isoforms (KITL1 and KITL2) in the adult human ovary, with both KITL protein isoforms present in granulosa cells and ovarian cortex. c-Kit and KITL proteins are expressed in multiple follicle cell types (granulosa, theca, stromal) throughout folliculogenesis, and oocytes express c-kit exclusively. Unlike animal models, expression of both proteins is less cell-type specific in humans, suggesting autocrine signaling occurs within the human ovary. RT-PCR for isoform detection, Western blot, immunohistochemistry in human ovarian tissue Journal of ovarian research Medium 26008799
2017 MAPK3/1 (ERK1/2) participates in primordial follicle activation through the mTORC1-KITL signaling pathway in pre-granulosa cells. MAPK3/1 inhibitor U0126 reduced follicle activation, decreased phosphorylation of TSC2, S6K1, rpS6, and reduced KITL expression. U0126 also decreased Akt phosphorylation and blocked Foxo3 nuclear export in oocytes, placing MAPK3/1 upstream of mTORC1-KITL in granulosa cells and KIT-PI3K signaling in oocytes. Ex vivo ovarian culture with MAPK3/1 inhibitor, Western blot for mTORC1 components, KITL expression analysis, PTEN inhibitor co-experiments, immunofluorescence for Foxo3 localization Journal of cellular physiology Medium 28218391
2017 Bone marrow adipocytes synthesize SCF (KITLG) and promote HSC maintenance and haematopoietic regeneration after irradiation or chemotherapy. Adipocyte-specific Scf deletion (using Adipoq-Cre/ER) inhibited haematopoietic regeneration, depleted HSCs (in tail vertebrae with abundant adipocytes), and reduced mouse survival after irradiation. SCF from LepR+ stromal cells also promoted regeneration. Conditional knockout (Adipoq-Cre/ER-driven Scf deletion), irradiation/5-FU models, HSC frequency measurement, survival curves Nature cell biology High 28714970
2019 SCF/cKIT signaling induces pathological ocular neovascularization through phosphorylation of glycogen synthase kinase-3β (GSK-3β) and enhancement of nuclear translocation of β-catenin and transcription of β-catenin target genes. Hypoxia upregulates cKIT in endothelial cells, enhancing the angiogenic response to SCF. Blockade of cKIT or SCF (using cKit mutant mice and anti-SCF IgG) suppressed pathological neovascularization in murine models. Hypoxia cell culture, cKit mutant mice, anti-SCF neutralizing antibody, β-catenin chemical inhibitors, in vivo retinopathy/choroidal neovascularization models, GSK-3β and β-catenin phosphorylation assays Arteriosclerosis, thrombosis, and vascular biology High 31434494
2019 SCF/c-Kit-activated signaling and angiogenesis require Gαi1 and Gαi3 proteins. In endothelial cells, Gαi1/3 associates with SCF-activated c-Kit, promotes c-Kit endocytosis, and facilitates binding of key adaptor proteins, thereby transducing downstream Akt-mTOR and ERK activation. Gαi1/3 silencing or KO attenuated SCF-induced HUVEC proliferation, migration, and tube formation in vitro and retinal angiogenesis in vivo. SCF/c-Kit expression was elevated in diabetic retinopathy, and SCF silencing inhibited pathological retinal angiogenesis. siRNA/shRNA knockdown, CRISPR KO, dominant-negative overexpression, endothelial-specific AAV shRNA in vivo, co-immunoprecipitation, signaling assays International journal of biological sciences High 37063428
2002 ENU-induced Kitl allelic series identified seven point mutations; five missense mutations affect residues within or near conserved alpha-helical domains of Kitl, establishing structural requirements for function. One allele causes a nonsense mutation with exon skipping, and one affects a splice site. ENU mutagenesis screen, sequencing of allelic series, structural mapping Genetics Medium 12242244
1997 PI3K p110delta is recruited to activated signaling complexes in leukocytes after treatment with stem cell factor (KITLG), together with p110alpha. Both associate with p85 adaptor subunits. Unlike p110alpha, p110delta does not phosphorylate p85 but harbors intrinsic autophosphorylation capacity, suggesting divergent regulatory capacities downstream of SCF/KIT. Immunoprecipitation, in vitro kinase assays, cytokine stimulation (SCF, IL-3, IL-4) Proceedings of the National Academy of Sciences of the United States of America Medium 9113989
2015 NRG1 and KITL (SCF) activate alternative pathways downstream of retinoic acid signaling in rat spermatogonia to support pre-meiotic spermatogonial differentiation without somatic cells. KITL prevents ERBB3-deficient spermatogonial degeneration upon differentiation. ERBB2 inhibitors blocked NRG1-dependent but not KITL-dependent spermatogonial development, demonstrating that KITL uses a distinct pathway from NRG1/ERBB2. Serum/somatic cell-free spermatogonial culture, ERBB2 pharmacological inhibitors, ERBB3-deficient spermatogonia, retinoic acid stimulation Cell death discovery Medium 26500786
2019 miR-27a directly targets and negatively regulates KITLG expression in Cashmere goat melanocytes. Luciferase reporter assays confirmed miR-27a binding to the KITLG 3'UTR. KITLG mRNA and protein were downregulated by miR-27a overexpression in vitro and in white goat skin (which has higher miR-27a expression), demonstrating a miR-27a → KITLG regulatory axis in pigmentation. Dual-luciferase reporter assay, miR-27a overexpression, qRT-PCR and Western blot, comparison of white vs brown skin Animal biotechnology Medium 31613171

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 JAZ repressor proteins are targets of the SCF(COI1) complex during jasmonate signalling. Nature 1808 17637677
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes & development 1218 20048001
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1990 Primary structure and functional expression of rat and human stem cell factor DNAs. Cell 795 2208279
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2006 Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer cell 692 16616334
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1997 Stem cell factor and hematopoiesis. Blood 644 9269751
2013 D14-SCF(D3)-dependent degradation of D53 regulates strigolactone signalling. Nature 635 24336215
2011 SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 564 21368833
2007 Genetic determinants of hair, eye and skin pigmentation in Europeans. Nature genetics 538 17952075
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2017 Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nature cell biology 408 28714970
2004 A hitchhiker's guide to the cullin ubiquitin ligases: SCF and its kin. Biochimica et biophysica acta 394 15571813
1997 P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proceedings of the National Academy of Sciences of the United States of America 383 9113989
2004 Signal transduction via the stem cell factor receptor/c-Kit. Cellular and molecular life sciences : CMLS 352 15526160
2014 SCF ubiquitin ligase-targeted therapies. Nature reviews. Drug discovery 293 25394868
1992 Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2. Molecular biology of the cell 287 1378327
2005 Regulation of the cell cycle by SCF-type ubiquitin ligases. Seminars in cell & developmental biology 284 15840441
2010 Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nature genetics 278 20543847
2007 cis-Regulatory changes in Kit ligand expression and parallel evolution of pigmentation in sticklebacks and humans. Cell 276 18083106
2007 Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell 271 17662946
2009 Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nature genetics 269 19483682
2012 Seventy-five genetic loci influencing the human red blood cell. Nature 266 23222517
2009 A genome-wide association study of testicular germ cell tumor. Nature genetics 261 19483681
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
1995 Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos. Biology of reproduction 185 8547494
2003 The role of Kit-ligand in melanocyte development and epidermal homeostasis. Pigment cell research 182 12753403
2004 Stem cell factor/c-kit signaling promotes the survival, migration, and capillary tube formation of human umbilical vein endothelial cells. The Journal of biological chemistry 176 14985355
2008 Identification of SCF ubiquitin ligase substrates by global protein stability profiling. Science (New York, N.Y.) 175 18988848
2003 Protein interaction analysis of SCF ubiquitin E3 ligase subunits from Arabidopsis. The Plant journal : for cell and molecular biology 175 12795696
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2004 The IAA1 protein is encoded by AXR5 and is a substrate of SCF(TIR1). The Plant journal : for cell and molecular biology 163 15546359
2001 Review: melanocyte migration and survival controlled by SCF/c-kit expression. The journal of investigative dermatology. Symposium proceedings 145 11764276
2013 Meta-analysis identifies four new loci associated with testicular germ cell tumor. Nature genetics 140 23666239
1998 Proteolysis and the G1-S transition: the SCF connection. Current opinion in genetics & development 140 9529603
2002 CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex. Proceedings of the National Academy of Sciences of the United States of America 136 12481031
2014 A molecular basis for classic blond hair color in Europeans. Nature genetics 134 24880339
2007 Differentiation 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. Stem cells (Dayton, Ohio) 133 17556598
2004 Kit and FcepsilonRI mediate unique and convergent signals for release of inflammatory mediators from human mast cells. Blood 133 15217825
2009 Molecular aspects of steroidogenic factor 1 (SF-1). Molecular and cellular endocrinology 125 19616058
2017 Composition and Regulation of the Cellular Repertoire of SCF Ubiquitin Ligases. Cell 117 29103612
1997 Met-HGF/SF: tumorigenesis, invasion and metastasis. Ciba Foundation symposium 115 9524767
2002 Requirement of Gab2 for mast cell development and KitL/c-Kit signaling. Blood 113 11861309
2007 Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage. Development (Cambridge, England) 104 17537799
2005 Mechanisms of tumor suppression by the SCF(Fbw7). Cell cycle (Georgetown, Tex.) 100 16131838
1999 SCF ubiquitin protein ligases and phosphorylation-dependent proteolysis. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 100 10582239
2016 SCF(Fbxo22)-KDM4A targets methylated p53 for degradation and regulates senescence. Nature communications 95 26868148
1997 HGF/SF in angiogenesis. Ciba Foundation symposium 91 9524773
2004 Smad4 protein stability is regulated by ubiquitin ligase SCF beta-TrCP1. The Journal of biological chemistry 87 14988407
2020 The Biology of F-box Proteins: The SCF Family of E3 Ubiquitin Ligases. Advances in experimental medicine and biology 86 31898225
2016 Recent advances in SCF ubiquitin ligase complex: Clinical implications. Biochimica et biophysica acta 85 27156687
2001 Interaction between cyclin T1 and SCF(SKP2) targets CDK9 for ubiquitination and degradation by the proteasome. Molecular and cellular biology 84 11689688
2016 SCF(Cyclin F)-dependent degradation of CDC6 suppresses DNA re-replication. Nature communications 83 26818844
2013 Genetically engineered mouse models for functional studies of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases. Cell research 79 23528706
2013 A new mechanism of RhoA ubiquitination and degradation: roles of SCF(FBXL19) E3 ligase and Erk2. Biochimica et biophysica acta 77 23871831
2014 DWARF3 participates in an SCF complex and associates with DWARF14 to suppress rice shoot branching. Plant & cell physiology 75 24616269
2000 The SCF ubiquitin ligase protein slimb regulates centrosome duplication in Drosophila. Current biology : CB 74 10996795
2017 MAPK3/1 participates in the activation of primordial follicles through mTORC1-KITL signaling. Journal of cellular physiology 72 28218391
2015 Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo. BMC cancer 72 26674205
2006 The Aspergillus nidulans F-box protein GrrA links SCF activity to meiosis. Molecular microbiology 69 16824096
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2016 SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development. The EMBO journal 57 27234298
2013 An SCF complex containing Fbxl12 mediates DNA damage-induced Ku80 ubiquitylation. Cell cycle (Georgetown, Tex.) 54 23324393
2022 A conformational switch in the SCF-D3/MAX2 ubiquitin ligase facilitates strigolactone signalling. Nature plants 53 35484202
2015 Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2. American journal of human genetics 53 26522471
2000 Stem cell factor (SCF) concentrations in peritoneal fluid of women with or without endometriosis. American journal of reproductive immunology (New York, N.Y. : 1989) 53 11076095
2011 KITLG mutations cause familial progressive hyper- and hypopigmentation. The Journal of investigative dermatology 52 21368769
2005 SCF(beta-TrCP1) controls Smad4 protein stability in pancreatic cancer cells. The American journal of pathology 51 15855639
1994 Expression and functional role of c-kit ligand (SCF) in human multiple myeloma cells. British journal of haematology 47 7529540
2005 Analysis of hypomorphic KitlSl mutants suggests different requirements for KITL in proliferation and migration of mouse primordial germ cells. Biology of reproduction 44 15917341
2006 Co expression of SCF and KIT in gastrointestinal stromal tumours (GISTs) suggests an autocrine/paracrine mechanism. British journal of cancer 43 16570044
2017 The stem cell factor (SCF)/c-KIT signalling in testis and prostate cancer. Journal of cell communication and signaling 42 28656507
2013 Role of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases in skin cancer. Journal of genetics and genomics = Yi chuan xue bao 42 23522382
2010 Adrenocortical development and cancer: focus on SF-1. Journal of molecular endocrinology 42 20200142
2021 The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. International journal of molecular sciences 38 34445249
2010 Hsk1- and SCF(Pof3)-dependent proteolysis of S. pombe Ams2 ensures histone homeostasis and centromere function. Developmental cell 38 20230746
2015 SCF, regulated by HIF-1α, promotes pancreatic ductal adenocarcinoma cell progression. PloS one 37 25799412
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2006 Association of genetic markers within the KIT and KITLG genes with human male infertility. Human reproduction (Oxford, England) 37 16905672
2023 Systemwide disassembly and assembly of SCF ubiquitin ligase complexes. Cell 36 37028429
2002 Seek and destroy: SCF ubiquitin ligases in mammalian cell cycle control. Cell cycle (Georgetown, Tex.) 36 12429941
2008 Involvement of the KIT/KITL signaling pathway in 4-vinylcyclohexene diepoxide-induced ovarian follicle loss in rats. Biology of reproduction 35 18448842
2012 Beyond steroidogenesis: novel target genes for SF-1 discovered by genomics. Molecular and cellular endocrinology 33 23168267
2009 SCF, BDNF, and Gas6 are regulators of growth plate chondrocyte proliferation and differentiation. Molecular endocrinology (Baltimore, Md.) 33 19897599
2017 Auxin signaling through SCFTIR1/AFBs mediates feedback regulation of IAA biosynthesis. Bioscience, biotechnology, and biochemistry 32 28406060
2017 NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis. Molecular cell 32 29149593
2017 The Arabidopsis ALF4 protein is a regulator of SCF E3 ligases. The EMBO journal 32 29233834
2016 Stem Cell Factor (SCF) is a putative biomarker of antidepressant response. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 32 27108110
2020 Pigment Intensity in Dogs is Associated with a Copy Number Variant Upstream of KITLG. Genes 30 31936656
2019 Notch and the pre-TCR coordinate thymocyte proliferation by induction of the SCF subunits Fbxl1 and Fbxl12. Nature immunology 30 31451788
2009 Adenovirus E1A inhibits SCF(Fbw7) ubiquitin ligase. The Journal of biological chemistry 30 19679664
2020 Skp, Cullin, F-box (SCF)-Met30 and SCF-Cdc4-Mediated Proteolysis of CENP-A Prevents Mislocalization of CENP-A for Chromosomal Stability in Budding Yeast. PLoS genetics 28 32032354
2019 SCFFBXW7/GSK3β-Mediated GFI1 Degradation Suppresses Proliferation of Gastric Cancer Cells. Cancer research 28 31289136
2015 Expression and localisation of c-kit and KITL in the adult human ovary. Journal of ovarian research 28 26008799
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2015 Isoform-specific SCF(Fbw7) ubiquitination mediates differential regulation of PGC-1α. Journal of cellular physiology 27 25204433
2014 PLCγ2 and PKC are important to myeloid lineage commitment triggered by M-SCF and G-CSF. Journal of cellular biochemistry 27 24038146
2018 MAPK signaling couples SCF-mediated degradation of translational regulators to oocyte meiotic progression. Proceedings of the National Academy of Sciences of the United States of America 26 29496961
2018 Insulin Regulates Adrenal Steroidogenesis by Stabilizing SF-1 Activity. Scientific reports 26 29567944
2019 The circadian E3 ligase complex SCFFBXL3+CRY targets TLK2. Scientific reports 25 30655559
2019 SCF (Stem Cell Factor) and cKIT Modulate Pathological Ocular Neovascularization. Arteriosclerosis, thrombosis, and vascular biology 25 31434494
2017 Effect of cadmium on kitl pre-mRNA alternative splicing in murine ovarian granulosa cells and its associated regulation by miRNAs. Journal of applied toxicology : JAT 25 28892167
2011 TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis. Cell death and differentiation 25 21233843
2023 SCF/c-Kit-activated signaling and angiogenesis require Gαi1 and Gαi3. International journal of biological sciences 24 37063428
2005 Molecular characterization of PDGFR-alpha/PDGF-A and c-KIT/SCF in gliosarcomas. Cellular oncology : the official journal of the International Society for Cellular Oncology 24 16373964
2015 Nobiletin, a polymethoxy flavonoid, reduced endothelin-1 plus SCF-induced pigmentation in human melanocytes. Photochemistry and photobiology 22 25488359
2014 Ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase Skp1-cullin-F-box ligase (SCF) interact through multiple conformations. The Journal of biological chemistry 22 25425648
2004 A specific endoplasmic reticulum export signal drives transport of stem cell factor (Kitl) to the cell surface. The Journal of biological chemistry 22 15475566
2020 SCFSNIPER7 controls protein turnover of unfoldase CDC48A to promote plant immunity. The New phytologist 21 33156518
2019 MiR-27a regulates WNT3A and KITLG expression in Cashmere goats with different coat colors. Animal biotechnology 21 31613171
2015 Cep68 can be regulated by Nek2 and SCF complex. European journal of cell biology 21 25704143
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2011 Polymorphism identification in the goat KITLG gene and association analysis with litter size. Animal genetics 21 22221032
2002 An allelic series of mutations in the kit ligand gene of mice. I. Identification of point mutations in seven ethylnitrosourea-induced Kitl(Steel) alleles. Genetics 21 12242244
2025 C-terminal amides mark proteins for degradation via SCF-FBXO31. Nature 20 39880951
2022 Autocrine/Paracrine Loop Between SCF+/c-Kit+ Mast Cells Promotes Cutaneous Melanoma Progression. Frontiers in immunology 20 35140718
2019 Spironolactone-induced XPB degradation depends on CDK7 kinase and SCFFBXL18 E3 ligase. Genes to cells : devoted to molecular & cellular mechanisms 20 30762924
2018 Genomic Analysis Suggests KITLG is Responsible for a Roan Pattern in two Pakistani Goat Breeds. The Journal of heredity 20 29099936
2018 Bmi1 Regulates IκBα Degradation via Association with the SCF Complex. Journal of immunology (Baltimore, Md. : 1950) 20 30209188
2005 Stem cell factor (SCF) and interleukin 3 (IL-3) in the sera of patients with colorectal cancer. Digestive diseases and sciences 20 15986847
2015 DNA damage regulates ARID1A stability via SCF ubiquitin ligase in gastric cancer cells. European review for medical and pharmacological sciences 19 26400522
2015 NRG1 and KITL Signal Downstream of Retinoic Acid in the Germline to Support Soma-Free Syncytial Growth of Differentiating Spermatogonia. Cell death discovery 19 26500786
2014 Stem cell factor (SCF) protects osteoblasts from oxidative stress through activating c-Kit-Akt signaling. Biochemical and biophysical research communications 19 25449280
2022 TDP-43 is a ubiquitylation substrate of the SCFcyclin F complex. Neurobiology of disease 18 35231559
2023 Structural and mechanistic insights into the CAND1-mediated SCF substrate receptor exchange. Molecular cell 17 37339624
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