Affinage

KITLG

Kit ligand · UniProt P21583

Length
273 aa
Mass
30.9 kDa
Annotated
2026-06-10
100 papers in source corpus 23 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KITLG (Kit ligand/Steel factor/SCF) is a dimeric growth factor that signals through the c-Kit receptor tyrosine kinase to control survival, proliferation, migration, and differentiation across hematopoietic, reproductive, pigmentary, and vascular lineages (PMID:1280935, PMID:17659849). Ligand binding induces c-Kit dimerization and autophosphorylation, engaging downstream PI3K/Akt, MAPK/ERK, JAK/STAT, Src, and PLC-γ cascades (PMID:17659849); in mast cells these outputs require the adaptor Gab2, whose loss impairs KITLG-induced ERK and Akt activation and markedly reduces mast cell numbers in vivo (PMID:11861309), while Gαi1/Gαi3 associate with activated c-Kit to drive receptor endocytosis and are required for SCF-induced Akt-mTOR and ERK signaling in endothelial cells (PMID:37063428). KITLG exists as membrane-bound and soluble isoforms with distinct activities, and its delivery to the cell surface depends on a C-terminal valine ER export signal that recruits it into COPII-coated ER exit sites (PMID:15475566, PMID:7684700). KITLG governs lineage-specific developmental programs: it drives FSH/cAMP-stimulated DNA synthesis and retinoic-acid-coupled differentiation in the spermatogonial lineage (PMID:7677988, PMID:26500786), supports ovarian follicle survival and primordial follicle activation downstream of a MAPK3/1→mTORC1→KITL axis (PMID:18448842, PMID:28218391), and controls spatiotemporal melanocyte migration and survival (PMID:11764276). In disease contexts, KITLG transcription is activated by HIF-1α binding to a promoter hypoxia response element to promote pancreatic tumor progression (PMID:25799412), and SCF/c-Kit signaling drives pathological ocular neovascularization through GSK-3β phosphorylation and β-catenin nuclear translocation (PMID:31434494); KITLG message is post-transcriptionally repressed by miR-27a and miR-34c via its 3'UTR (PMID:31613171, PMID:26674205). Loss-of-function or trafficking-defective KITLG mutations cause pigmentation disorders, hearing loss, and Waardenburg syndrome type 2 (PMID:26522471).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1992 High

    Established that the KITLG/c-Kit axis is the essential, non-redundant determinant of a defined cell lineage in vivo, anchoring KITLG as a developmental growth factor rather than a modulatory one.

    Evidence Genetic W/Wv c-Kit loss-of-function mice with mast cell reconstitution across tissues

    PMID:1280935

    Open questions at the time
    • Does not resolve which downstream signaling branches mediate each mast cell behavior
    • Phenotype assessed via receptor loss, not direct ligand manipulation
  2. 1993 Medium

    Defined how KITLG expression is hormonally controlled and showed soluble ligand alone drives a specific proliferative response, establishing a tissue context (testis) for KITLG action.

    Evidence Sertoli cell culture with FSH/cAMP, isoform-specific PCR, and [3H]-thymidine incorporation in type A spermatogonia

    PMID:7677988

    Open questions at the time
    • Downstream c-Kit signaling pathway in spermatogonia not dissected
    • Relative roles of soluble vs membrane isoform in vivo unresolved
  3. 1993 Medium

    Demonstrated functional non-equivalence of the membrane-bound and soluble KITLG isoforms, showing that membrane presentation can be required to sustain c-Kit-dependent proliferation.

    Evidence FDC-P1/c-Kit fibroblast co-culture using Sl/Sld mutant fibroblasts producing only soluble SLF

    PMID:7684700

    Open questions at the time
    • Structural basis for differential isoform activity not defined
    • Mechanism of GM-CSF/IL-3-induced c-Kit downregulation unexplained
  4. 2001 Medium

    Showed that spatiotemporally restricted KITLG expression patterns the migration and survival of a developing lineage, distinguishing c-Kit-dependent from c-Kit-independent stages.

    Evidence SCF transgenic mice, anti-c-Kit antibody blockade, and Sl/W mutant analysis of melanocyte development

    PMID:11764276

    Open questions at the time
    • Molecular signaling controlling each developmental stage not mapped
    • Source cells of KITLG at each stage not fully defined
  5. 2002 High

    Placed an intracellular adaptor (Gab2) downstream of c-Kit, identifying a required node converting receptor activation into the ERK and Akt outputs needed for mast cell development.

    Evidence Gab2 knockout mice and bone marrow-derived mast cell culture with phospho-ERK/Akt readouts

    PMID:11861309

    Open questions at the time
    • How Gab2 is recruited to c-Kit not defined
    • Whether Gab2 dependence generalizes to other KITLG-responsive lineages unknown
  6. 2002 Low

    Linked KITLG to cooperative cytokine signaling and specific cell-cycle/transcriptional effectors in primitive hematopoietic cell expansion.

    Evidence MO7e-G synergy system with p27Kip1 and STAT3 phosphorylation Westerns (review/summary paper)

    PMID:12152985

    Open questions at the time
    • Reported in a summary paper with limited methodological detail
    • Direct causal link between STAT3/p27 changes and expansion not demonstrated
  7. 2002 Medium

    Mapped functional KITLG residues onto conserved alpha-helical domains, providing the first structure-function correlation for the ligand.

    Evidence ENU mutagenesis allelic series at the Steel locus with phenotype-severity correlation

    PMID:12242244 PMID:12242245

    Open questions at the time
    • Biochemical effect of each missense mutation on c-Kit binding not measured
    • No high-resolution structure to interpret residue roles
  8. 2004 High

    Identified the molecular determinant controlling KITLG surface delivery, showing a C-terminal valine acts as an ER export signal recruiting KITLG into COPII vesicles.

    Evidence Cytoplasmic-tail deletion/substitution mutagenesis with COPII colocalization and surface biotinylation/transport assays

    PMID:15475566

    Open questions at the time
    • COPII coat component that reads the valine signal not identified
    • Whether trafficking is regulated to tune surface ligand levels unknown
  9. 2007 Low

    Consolidated the receptor-proximal mechanism: KITLG drives c-Kit dimerization and autophosphorylation feeding into multiple defined signaling pathways.

    Evidence Review integrating c-Kit dimerization, autophosphorylation, and downstream pathway and juxtamembrane mutation analyses

    PMID:17659849

    Open questions at the time
    • No primary new data in this paper
    • Pathway selection across cell types not addressed
  10. 2008 Medium

    Extended KITLG function into the tumor microenvironment, showing concentration-dependent control of mast cell chemotaxis versus activation and downstream immunosuppression.

    Evidence In vitro mast cell chemotaxis/activation assays, NF-κB/AP-1 reporters, and Treg suppression assays with recombinant SCF

    PMID:18524989

    Open questions at the time
    • In vivo relevance of the concentration thresholds not established
    • Whether soluble or membrane KITLG drives this in tumors unclear
  11. 2008 Medium

    Demonstrated that KITLG supplementation rescues follicle loss, establishing KIT/KITL signaling as a survival factor for ovarian primordial and primary follicles.

    Evidence In vivo VCD dosing plus in vitro ovarian culture with exogenous KITL rescue, microarray, qPCR, Western blot

    PMID:18448842

    Open questions at the time
    • Signaling pathway mediating follicle survival not dissected here
    • Mechanism of compensatory Kitl upregulation unknown
  12. 2009 Medium

    Showed KITLG can act as a brake on proliferation and a driver of differentiation in a non-hematopoietic tissue, attenuating IGF-I/ERK signaling in chondrocytes.

    Evidence Growth plate chondrocyte and ATDC5 cultures with proliferation, ERK1/2 phospho-Westerns, and differentiation markers

    PMID:19897599

    Open questions at the time
    • Mechanism by which KITLG attenuates IGF-I-driven ERK not defined
    • In vivo skeletal relevance not tested
  13. 2011 Low

    Identified KITLG mutations in a conserved beta-strand as a cause of human progressive pigmentation disorders, translating ligand structure-function to human disease.

    Evidence Genome-wide linkage and mutation co-segregation analysis across seven families with FPHH

    PMID:21368769

    Open questions at the time
    • No functional validation of mutation effect on c-Kit activation in this study
    • Mechanism (gain vs loss of function) not resolved
  14. 2015 Medium

    Established KITLG as a Mendelian deafness/Waardenburg gene and linked specific mutations to defective surface localization or impaired soluble ligand shedding, distinguishing loss-of-function from dominant-negative mechanisms.

    Evidence Transfection of mutant constructs with surface localization assays and ELISA for soluble KITLG

    PMID:26522471

    Open questions at the time
    • Shedding machinery affected by the WS2 mutation not identified
    • In vivo confirmation of dominant-negative mechanism lacking
  15. 2015 Medium

    Showed KITLG operates as an alternative, ERBB-independent effector pathway for retinoic-acid-induced spermatogonial differentiation, refining its germline role.

    Evidence Soma-free spermatogonial culture with ERBB2 inhibitor and ERBB3-deficient cells under retinoic acid

    PMID:26500786

    Open questions at the time
    • Intracellular signaling distinguishing KITL from NRG1/ERBB pathways not mapped
    • Source of KITL in soma-free system unclear
  16. 2015 Medium

    Defined direct transcriptional control of KITLG by HIF-1α, placing the ligand downstream of hypoxia signaling to promote tumor progression.

    Evidence ChIP and luciferase reporter on the KITLG promoter HRE, RNAi, and SCF rescue after HIF-1α knockdown in PDAC with xenografts

    PMID:25799412

    Open questions at the time
    • Whether tumor cell-autonomous or paracrine c-Kit signaling mediates the effect not resolved
    • Single cancer context
  17. 2015 Medium

    Identified miR-34c as a direct 3'UTR repressor of KITLG, embedding the ligand in a resveratrol-responsive anti-cancer regulatory axis.

    Evidence Luciferase 3'UTR assay, lentiviral miR-34c gain/loss-of-function with KITLG readout, colorectal xenografts

    PMID:26674205

    Open questions at the time
    • Physiological contexts where miR-34c sets KITLG levels not defined
    • Other 3'UTR regulators not surveyed
  18. 2017 Medium

    Ordered MAPK3/1 upstream of an mTORC1-KITL axis in primordial follicle activation, linking somatic ERK signaling to oocyte Akt/Foxo3 control via the ligand.

    Evidence Neonatal ovary culture with U0126 and PTEN inhibitor, Western blots of Tsc2/S6K1/rpS6/Akt, and follicle counting

    PMID:28218391

    Open questions at the time
    • Direct transcriptional mechanism by which mTORC1 controls KITL not shown
    • In vivo genetic confirmation lacking
  19. 2017 Low

    Associated environmental cadmium with altered kitl isoform ratios via splicing and a candidate miRNA program, implicating post-transcriptional control of KITLG isoforms.

    Evidence Granulosa cell Cd exposure with isoform-specific RT-PCR and miRNA microarray

    PMID:28892167

    Open questions at the time
    • Associative miRNA-splicing correlation without functional validation
    • No demonstration that named miRNAs control kitl splicing directly
  20. 2019 High

    Defined a discrete biochemical mechanism for KITLG-driven pathological angiogenesis through GSK-3β phosphorylation and β-catenin nuclear translocation, validated genetically and pharmacologically in vivo.

    Evidence cKit mutant mice, anti-SCF antibody, β-catenin inhibitors/agonist rescue, GSK-3β/β-catenin Westerns, OIR and laser-CNV models

    PMID:31434494

    Open questions at the time
    • How c-Kit activation links to GSK-3β phosphorylation mechanistically not detailed
    • Relative contribution of canonical PI3K/MAPK branches not separated
  21. 2019 Medium

    Confirmed miR-27a as a direct 3'UTR repressor of KITLG that inversely correlates with KITLG in pigmented tissue, reinforcing post-transcriptional control of ligand levels.

    Evidence Luciferase 3'UTR assay, miR-27a overexpression in HEK-293T, and Western/qRT-PCR in goat skin

    PMID:31613171

    Open questions at the time
    • Functional consequence for pigmentation not directly tested
    • Whether miR-27a regulation operates in human tissue unknown
  22. 2023 High

    Identified Gαi1/Gαi3 as physical partners of activated c-Kit required for receptor endocytosis and propagation of SCF-induced Akt-mTOR and ERK signaling, revealing a heterotrimeric G-protein requirement in this RTK pathway.

    Evidence Reciprocal Co-IP of Gαi1/3 with c-Kit, siRNA/KO/dominant-negative perturbation, phospho-Westerns, HUVEC assays, and AAV-shRNA in retinal angiogenesis models

    PMID:37063428

    Open questions at the time
    • How Gαi proteins are recruited to c-Kit not defined
    • Whether this requirement extends beyond endothelial cells unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct KITLG-c-Kit signaling outputs (PI3K/Akt vs ERK vs JAK/STAT) are selected to produce lineage-specific outcomes across hematopoietic, germline, melanocyte, and vascular contexts remains unresolved.
  • No unified model linking isoform choice and adaptor usage to pathway selection
  • No structural model of the human KITLG-c-Kit complex in the corpus
  • Tissue-specific determinants of soluble vs membrane KITLG signaling undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1474165 Reproduction 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
GAB2GNAI1GNAI3KIT

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 FSH and its intracellular mediator cAMP increase mRNA levels for Steel factor (SLF/KITLG) — both the soluble and transmembrane isoforms — in cultured mouse Sertoli cells. Soluble recombinant SLF selectively stimulates DNA synthesis in type A spermatogonia in a dose-dependent manner, independent of serum. Primary Sertoli cell culture with FSH/cAMP treatment, PCR for isoform-specific mRNA detection, [3H]-thymidine incorporation assay in isolated spermatogonial populations, autoradiography Developmental biology Medium 7677988
1992 SCF (KITLG) is the major migration, survival, proliferation, and maturation factor for mast cell precursors acting through the c-Kit tyrosine kinase receptor. W/Wv mice lacking functional c-Kit virtually lack tissue mast cells, establishing that the KITLG/c-Kit axis is essential for mast cell development in vivo. Genetic mouse models (W/Wv loss-of-function), adoptive transfer / mast cell reconstitution experiments in multiple tissues Annals of the New York Academy of Sciences High 1280935
1993 Membrane-bound SLF (KITLG transmembrane isoform) — but not soluble SLF — can support sustained proliferation of FDC-P1 myeloid cells expressing c-Kit on fibroblast co-culture. The Sl/Sld mutant fibroblasts producing only soluble SLF fail to support these cells, demonstrating a functional distinction between membrane-bound and soluble KITLG isoforms. GM-CSF and IL-3 downregulate surface c-Kit expression in a unidirectional manner, reducing responsiveness to SLF. Fibroblast co-culture with neutralizing antibodies against GM-CSF, Sl/Sld mutant fibroblasts (soluble SLF only), cell adaptation assay, c-kit mRNA quantification, surface c-Kit protein measurement Experimental hematology Medium 7684700
2002 Gab2 adaptor protein is required for KitL/c-Kit signaling and mast cell development. In Gab2-deficient mice, mast cell numbers are markedly reduced, and bone marrow-derived mast cells grow poorly in response to KITLG. KITLG-induced ERK MAP kinase and Akt activation are both impaired in Gab2-deficient cells, placing Gab2 downstream of c-Kit in the KITLG signaling cascade. Gab2 knockout mice, bone marrow-derived mast cell culture with KitL, flow cytometry for mast cell numbers, ERK and Akt phosphorylation assays Blood High 11861309
2001 KITLG (SCF) and its receptor c-Kit control multiple stages of melanocyte migration and survival during mouse ontogeny. Spatiotemporally specific expression of SCF in the dermis is required for c-Kit-dependent melanocyte colonization; SCF transgene expression rescues specific stages of melanocyte development, and functional c-Kit blockade by monoclonal antibody identifies distinct c-Kit-dependent and c-Kit-independent developmental stages. SCF transgenic mice, anti-c-Kit monoclonal antibody functional blockade, white spotting mutant (Sl/W) mouse analysis, immunohistochemistry The journal of investigative dermatology. Symposium proceedings Medium 11764276
2002 Seven ENU-induced point mutations in Kitl (KITLG) at the Steel locus were characterized; five are missense mutations each affecting residues within or near conserved alpha-helical domains of KITLG. This establishes that the helical domain residues are structurally required for KITLG function, as homozygous mutations cause severe anemia and lethality correlated with mutation severity. ENU mutagenesis screen, DNA sequencing of Kitl alleles, phenotypic analysis of peripheral blood and pigmentation in heterozygous and homozygous mice Genetics Medium 12242244 12242245
2002 SCF (KITLG) synergizes with G-CSF to promote expansion of primitive hematopoietic cells and peripheral blood progenitor cell mobilization. This synergy involves downregulation of p27Kip1 and independent phosphorylation of STAT3 on both tyrosine and serine residues as key intracellular biochemical events. MO7e-G cell system recapitulating SCF/G-CSF synergy, Western blot for p27Kip1, STAT3 phosphorylation (tyrosine and serine) analysis Leukemia & lymphoma Low 12152985
2004 Intracellular trafficking of KITLG (Kit ligand) to the cell surface is controlled at the level of the endoplasmic reticulum (ER) by a C-terminal valine residue in the cytoplasmic tail, positioned 19–36 amino acids from the transmembrane/cytoplasmic domain border. This valine functions as a specific ER export signal mediating recruitment of KITLG into COPII-coated ER exit sites and ER-to-Golgi vesicular transport. Deletion or substitution of this valine causes ER accumulation and reduced cell surface transport. Deletion/substitution mutagenesis of Kitl cytoplasmic tail, GFP-VSV-G fusion construct live imaging, COPII colocalization, cell surface biotinylation/transport assays The Journal of biological chemistry High 15475566
2007 KITLG (SCF) binding to c-Kit induces rapid and complete receptor dimerization, leading to activation by autophosphorylation of the catalytic tyrosine kinase domain. This generates signal transduction regulating cell growth through multiple pathways including PI3K, Src, JAK/STAT, PLC-γ, and MAPK. Gain-of-function mutations in the inhibitory juxtamembrane domain (exon 11) of c-Kit constitutively activate signaling independent of KITLG. Review integrating biochemical assays of c-Kit dimerization, autophosphorylation, and downstream pathway activation; mutational analysis of juxtamembrane domain Gene Low 17659849
2008 Tumor-derived KITLG (SCF) mediates mast cell chemotactic migration (at low concentrations) and activation (at higher concentrations) via c-Kit receptor on mast cells. Activated mast cells upregulate NF-κB and AP-1 activity in tumor cells, increase IL-17 expression, release adenosine, and expand T regulatory cells, thereby promoting immunosuppression. This establishes KITLG as the initiating signal for tumor microenvironment remodeling by mast cells. In vitro mast cell chemotaxis assays with recombinant SCF, cytokine measurement, NF-κB/AP-1 reporter assays, T cell suppression assays, flow cytometry Blood Medium 18524989
2008 KITLG (KIT ligand/KITL) attenuates 4-vinylcyclohexene diepoxide (VCD)-induced primordial and primary follicle loss in rat ovaries. VCD decreases Kit expression and increases Kitl mRNA and protein, suggesting compensatory upregulation. Addition of exogenous KITL to ovarian cultures during VCD exposure rescues follicle loss, establishing that KIT/KITL signaling is critical for follicular survival. In vivo VCD dosing and in vitro ovarian culture, microarray analysis, qPCR, Western blot, growth factor rescue experiments in primary ovarian cultures Biology of reproduction Medium 18448842
2009 SCF (KITLG) inhibits IGF-I-mediated proliferation in isolated growth plate chondrocytes by attenuating ERK1/2 activation, and promotes chondrocyte differentiation in ATDC5 cells. KITLG signals through its receptor KIT to modulate the pace of differentiation at the growth plate. Chondrocyte isolation and culture, proliferation assays, ERK1/2 phosphorylation Western blot, ATDC5 differentiation assay with collagen X/II/aggrecan markers Molecular endocrinology Medium 19897599
2011 Mutations in KITLG cause familial progressive hyper- and hypopigmentation (FPHH). Three missense mutations (including p.Val33Ala and p.Thr34Pro) located in a conserved β-strand of KITLG co-segregate with disease, suggesting this structural region is important for activation of the c-Kit receptor. The same gene harbors mutations causing familial progressive hyperpigmentation (FPH) and likely DUH2, establishing KITLG as an important modulator of skin pigmentation. Genome-wide linkage analysis, mutation screening, co-segregation analysis in seven families The Journal of investigative dermatology Low 21368769
2015 Mutations in KITLG cause non-syndromic unilateral/asymmetric hearing loss and Waardenburg syndrome type 2. In vitro studies showed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting loss-of-function pathogenicity. The p.Leu104Val mutation associated with WS2 produces a transmembrane KITLG that localizes to the cell membrane but yields reduced secreted soluble KITLG, suggesting a dominant-negative or gain-of-function effect via impaired shedding. Cell surface localization assay (immunofluorescence/flow cytometry), ELISA for soluble KITLG in conditioned medium, transfection of mutant constructs American journal of human genetics Medium 26522471
2015 HIF-1α directly binds to the hypoxia response element (HRE) region of the KITLG promoter under hypoxic conditions, activating KITLG transcription in pancreatic ductal adenocarcinoma cells. KITLG knockdown under hypoxia reduces cell proliferation and invasion, and exogenous SCF (KITLG) rescues these defects after HIF-1α knockdown, placing KITLG downstream of HIF-1α in promoting PDAC progression. Chromatin immunoprecipitation (ChIP) assay, luciferase reporter assay, RNAi knockdown, Western blot, colony formation and Transwell invasion assays, in vivo xenograft with digoxin (HIF-1α inhibitor) PloS one Medium 25799412
2015 KITL (Kit ligand) supports retinoic acid-induced spermatogonial differentiation in a soma-free culture system. KITL activates an alternative pathway downstream of retinoic acid that is distinct from NRG1/ERBB2/ERBB3 signaling — ERBB2 inhibitors do not block KITL-dependent spermatogonial development, and KITL prevents degeneration of ERBB3-deficient spermatogonia upon differentiation. Soma-free spermatogonial culture with defined factors, ERBB2 inhibitor treatment, ERBB3-deficient cells, retinoic acid treatment, morphological and marker assessment of differentiation Cell death discovery Medium 26500786
2017 MAPK3/1 (ERK1/2) participates in primordial follicle activation through a mTORC1-KITL signaling axis in pre-granulosa cells. MAPK3/1 inhibition with U0126 reduces follicle activation, decreases phosphorylation of Tsc2, S6K1, and rpS6, and reduces KITL expression. The reduction in KITL leads to decreased Akt phosphorylation in oocytes and impaired Foxo3 nuclear export, linking MAPK3/1 upstream of mTORC1-KITL signaling. Ex vivo neonatal ovary culture with U0126 (MAPK3/1 inhibitor) and bpV(HOpic) (PTEN inhibitor), Western blot, immunofluorescence, follicle counting Journal of cellular physiology Medium 28218391
2019 SCF (KITLG)/cKIT signaling induces pathological ocular neovascularization mechanistically through phosphorylation of glycogen synthase kinase-3β (GSK-3β), enhancement of β-catenin nuclear translocation, and transcription of β-catenin target genes related to angiogenesis. Hypoxia upregulates cKIT expression in endothelial cells, enhancing their angiogenic response to SCF. In vivo, anti-SCF neutralizing IgG and cKit mutant mice show substantially suppressed pathological ocular neovascularization. cKit mutant mice, anti-SCF neutralizing antibody, β-catenin chemical inhibitors, Western blot for GSK-3β phosphorylation and β-catenin, oxygen-induced retinopathy and laser-induced CNV models, β-catenin agonist rescue experiment Arteriosclerosis, thrombosis, and vascular biology High 31434494
2023 Gαi1 and Gαi3 associate with SCF (KITLG)-activated c-Kit in endothelial cells, promote c-Kit endocytosis and binding of key adaptor proteins, and are required for downstream SCF/c-Kit signal transduction. SCF-induced Akt-mTOR and ERK activation is robustly attenuated by Gαi1/3 silencing or dominant-negative mutations, and SCF-induced HUVEC proliferation, migration, and capillary tube formation are suppressed. In vivo endothelial knockdown of Gαi1/3 reduces SCF-induced retinal angiogenesis. Co-immunoprecipitation of Gαi1/3 with c-Kit, Gαi1/3 siRNA/KO/dominant-negative/overexpression, Akt and ERK phosphorylation Western blots, HUVEC functional assays, intravitreous AAV-shRNA injection in mice, streptozotocin diabetic retinopathy model International journal of biological sciences High 37063428
2017 Cadmium (Cd) exposure alters the kitl1/kitl2 mRNA ratio through changes in alternative splicing of kitl pre-mRNA in murine ovarian granulosa cells, associated with altered expression of 29 miRNAs. miRNAs including mmu-miR-27a-3p, mmu-miR-34b-5p, mmu-miR-297a-3p, mmu-miR-129-5p, and mmu-miR-107-3p show expression changes consistent with a regulatory role in kitl alternative splicing. In vitro granulosa cell Cd exposure, isoform-specific RT-PCR, miRNA microarray, bioinformatics pathway analysis, qPCR validation of miRNAs Journal of applied toxicology Low 28892167
2019 miR-27a directly targets the 3'UTR of KITLG mRNA, negatively regulating KITLG mRNA and protein expression. Overexpression of miR-27a in HEK-293T cells reduces KITLG expression, and dual-luciferase reporter assays confirm direct miR-27a binding to the KITLG 3'UTR. In goat skin, miR-27a expression is higher in white vs. brown animals and inversely correlates with KITLG expression. Luciferase 3'UTR reporter assay, miR-27a overexpression in HEK-293T cells, Western blot and qRT-PCR in goat skin, in vivo/in vitro concordance Animal biotechnology Medium 31613171
2015 miR-34c directly targets KITLG mRNA, and resveratrol upregulates miR-34c to suppress KITLG expression in colorectal cancer cells. Lentiviral knockdown of miR-34c rescues KITLG and partially reverses the anti-cancer effects of resveratrol, while miR-34c overexpression reduces KITLG. The anti-CRC effect of resveratrol is partially mediated through the miR-34c-KITLG axis, confirmed in xenograft models. Lentiviral miR-34c overexpression/inhibitor, Western blot and qPCR for KITLG, xenograft mouse model, methylation-specific PCR for miR-34c promoter BMC cancer Medium 26674205

Source papers

Stage 0 corpus · 100 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 1819 17637677
2010 A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes & development 1230 20048001
1999 SCF and Cullin/Ring H2-based ubiquitin ligases. Annual review of cell and developmental biology 1015 10611969
2013 D14-SCF(D3)-dependent degradation of D53 regulates strigolactone signalling. Nature 642 24336215
2004 A hitchhiker's guide to the cullin ubiquitin ligases: SCF and its kin. Biochimica et biophysica acta 395 15571813
2014 SCF ubiquitin ligase-targeted therapies. Nature reviews. Drug discovery 296 25394868
2005 Regulation of the cell cycle by SCF-type ubiquitin ligases. Seminars in cell & developmental biology 286 15840441
2009 Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nature genetics 270 19483682
2008 SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood 269 18524989
2004 APC/C and SCF: controlling each other and the cell cycle. Current biology : CB 237 15380093
1998 SCF and APC: the Yin and Yang of cell cycle regulated proteolysis. Current opinion in cell biology 220 9914180
1993 Follicle-stimulating hormone induction of steel factor (SLF) mRNA in mouse Sertoli cells and stimulation of DNA synthesis in spermatogonia by soluble SLF. Developmental biology 182 7677988
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
2005 SCF-mediated protein degradation and cell cycle control. Oncogene 153 15838520
2001 Review: melanocyte migration and survival controlled by SCF/c-kit expression. The journal of investigative dermatology. Symposium proceedings 145 11764276
1998 Proteolysis and the G1-S transition: the SCF connection. Current opinion in genetics & development 140 9529603
2011 SCF E3 ubiquitin ligases as anticancer targets. Current cancer drug targets 121 21247385
2017 Composition and Regulation of the Cellular Repertoire of SCF Ubiquitin Ligases. Cell 120 29103612
2002 Requirement of Gab2 for mast cell development and KitL/c-Kit signaling. Blood 113 11861309
1999 SCF ubiquitin protein ligases and phosphorylation-dependent proteolysis. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 101 10582239
2005 Mechanisms of tumor suppression by the SCF(Fbw7). Cell cycle (Georgetown, Tex.) 100 16131838
2016 SCF(Fbxo22)-KDM4A targets methylated p53 for degradation and regulates senescence. Nature communications 97 26868148
2020 The Biology of F-box Proteins: The SCF Family of E3 Ubiquitin Ligases. Advances in experimental medicine and biology 89 31898225
2016 Recent advances in SCF ubiquitin ligase complex: Clinical implications. Biochimica et biophysica acta 85 27156687
2016 SCF(Cyclin F)-dependent degradation of CDC6 suppresses DNA re-replication. Nature communications 84 26818844
2013 Genetically engineered mouse models for functional studies of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases. Cell research 79 23528706
2017 MAPK3/1 participates in the activation of primordial follicles through mTORC1-KITL signaling. Journal of cellular physiology 74 28218391
2000 The SCF ubiquitin ligase protein slimb regulates centrosome duplication in Drosophila. Current biology : CB 74 10996795
2015 Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo. BMC cancer 73 26674205
2018 SCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis. Nature communications 66 30177679
2007 Role of c-kit/SCF in cause and treatment of gastrointestinal stromal tumors (GIST). Gene 66 17659849
2006 F-box proteins: more than baits for the SCF? Cell division 66 17166256
2011 Variants in or near KITLG, BAK1, DMRT1, and TERT-CLPTM1L predispose to familial testicular germ cell tumour. Journal of medical genetics 64 21617256
2006 AhSSK1, a novel SKP1-like protein that interacts with the S-locus F-box protein SLF. The Plant journal : for cell and molecular biology 64 16709194
2004 c-kit and SCF expression in normal and tumor breast tissue. Breast cancer research and treatment 63 14997053
2016 SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development. The EMBO journal 57 27234298
2007 Comparison of Petunia inflata S-Locus F-box protein (Pi SLF) with Pi SLF like proteins reveals its unique function in S-RNase based self-incompatibility. The Plant cell 57 18024566
2013 An SCF complex containing Fbxl12 mediates DNA damage-induced Ku80 ubiquitylation. Cell cycle (Georgetown, Tex.) 55 23324393
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 High-level expression and purification of recombinant SCF ubiquitin ligases. Methods in enzymology 46 16275325
1992 Analyzing mast cell development and function using mice carrying mutations at W/c-kit or Sl/MGF (SCF) loci. Annals of the New York Academy of Sciences 46 1280935
2014 Crumbs promotes expanded recognition and degradation by the SCF(Slimb/β-TrCP) ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 45 24778256
2011 Associations between variants in KITLG, SPRY4, BAK1, and DMRT1 and pediatric germ cell tumors. Genes, chromosomes & cancer 44 22072546
2017 The stem cell factor (SCF)/c-KIT signalling in testis and prostate cancer. Journal of cell communication and signaling 43 28656507
2011 The genetic determination of skin pigmentation: KITLG and the KITLG/c-Kit pathway as key players in the onset of human familial pigmentary diseases. The Journal of investigative dermatology 43 21566575
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
2002 The synergy between stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF): molecular basis and clinical relevance. Leukemia & lymphoma 41 12152985
2021 The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. International journal of molecular sciences 40 34445249
2007 Expression of 10 S-class SLF-like genes in Nicotiana alata pollen and its implications for understanding the pollen factor of the S locus. Genetics 40 17947432
2014 The SCF/c-KIT system in the male: Survival strategies in fertility and cancer. Molecular reproduction and development 39 25359157
2008 The SCF FSN-1 ubiquitin ligase controls germline apoptosis through CEP-1/p53 in C. elegans. Cell death and differentiation 39 18340346
2023 Systemwide disassembly and assembly of SCF ubiquitin ligase complexes. Cell 38 37028429
2015 SCF, regulated by HIF-1α, promotes pancreatic ductal adenocarcinoma cell progression. PloS one 38 25799412
2015 SCF(β-TRCP) promotes cell growth by targeting PR-Set7/Set8 for degradation. Nature communications 38 26666832
2010 Hsk1- and SCF(Pof3)-dependent proteolysis of S. pombe Ams2 ensures histone homeostasis and centromere function. Developmental cell 38 20230746
2020 Targeting SCF E3 Ligases for Cancer Therapies. Advances in experimental medicine and biology 37 31898226
2016 The SCF-type E3 Ubiquitin Ligases as Cancer Targets. Current cancer drug targets 37 26560120
2002 Seek and destroy: SCF ubiquitin ligases in mammalian cell cycle control. Cell cycle (Georgetown, Tex.) 36 12429941
1993 Responses of the murine myeloid cell line FDC-P1 to soluble and membrane-bound forms of steel factor (SLF). Experimental hematology 36 7684700
2008 Involvement of the KIT/KITL signaling pathway in 4-vinylcyclohexene diepoxide-induced ovarian follicle loss in rats. Biology of reproduction 35 18448842
2009 SCF, BDNF, and Gas6 are regulators of growth plate chondrocyte proliferation and differentiation. Molecular endocrinology (Baltimore, Md.) 34 19897599
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 33 27108110
2008 SCF(Fbx4/alphaB-crystallin) E3 ligase: when one is not enough. Cell cycle (Georgetown, Tex.) 33 18818515
2017 Auxin signaling through SCFTIR1/AFBs mediates feedback regulation of IAA biosynthesis. Bioscience, biotechnology, and biochemistry 32 28406060
2019 Notch and the pre-TCR coordinate thymocyte proliferation by induction of the SCF subunits Fbxl1 and Fbxl12. Nature immunology 30 31451788
2015 Expression and localisation of c-kit and KITL in the adult human ovary. Journal of ovarian research 30 26008799
2012 Identification of a canonical SCF(SLF) complex involved in S-RNase-based self-incompatibility of Pyrus (Rosaceae). Plant molecular biology 30 23263858
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 29 32032354
2019 SCFFBXW7/GSK3β-Mediated GFI1 Degradation Suppresses Proliferation of Gastric Cancer Cells. Cancer research 28 31289136
2016 Skp1: Implications in cancer and SCF-oriented anti-cancer drug discovery. Pharmacological research 28 27238229
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
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 26 28892167
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
2007 SCF Fbx4/alphaB-crystallin cyclin D1 ubiquitin ligase: a license to destroy. Cell division 25 17224055
2023 SCF/c-Kit-activated signaling and angiogenesis require Gαi1 and Gαi3. International journal of biological sciences 24 37063428
2002 An allelic series of mutations in the Kit ligand gene of mice. II. Effects of ethylnitrosourea-induced Kitl point mutations on survival and peripheral blood cells of Kitl(Steel) mice. Genetics 24 12242245
2020 SCFSNIPER7 controls protein turnover of unfoldase CDC48A to promote plant immunity. The New phytologist 23 33156518
2025 C-terminal amides mark proteins for degradation via SCF-FBXO31. Nature 22 39880951
2019 MiR-27a regulates WNT3A and KITLG expression in Cashmere goats with different coat colors. Animal biotechnology 22 31613171
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
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 22 12242244
2019 Spironolactone-induced XPB degradation depends on CDK7 kinase and SCFFBXL18 E3 ligase. Genes to cells : devoted to molecular & cellular mechanisms 21 30762924
2012 DEPTOR ubiquitination and destruction by SCF(β-TrCP). American journal of physiology. Endocrinology and metabolism 21 22454292
2022 Autocrine/Paracrine Loop Between SCF+/c-Kit+ Mast Cells Promotes Cutaneous Melanoma Progression. Frontiers in immunology 20 35140718
2018 Genomic Analysis Suggests KITLG is Responsible for a Roan Pattern in two Pakistani Goat Breeds. The Journal of heredity 20 29099936
2023 Structural and mechanistic insights into the CAND1-mediated SCF substrate receptor exchange. Molecular cell 19 37339624
2022 TDP-43 is a ubiquitylation substrate of the SCFcyclin F complex. Neurobiology of disease 19 35231559
2020 High expression of KITLG is a new hallmark activating the MAPK pathway in type A and AB thymoma. Thoracic cancer 19 32463597
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
2019 Stratifin Inhibits SCFFBW7 Formation and Blocks Ubiquitination of Oncoproteins during the Course of Lung Adenocarcinogenesis. Clinical cancer research : an official journal of the American Association for Cancer Research 18 30728155
2014 Ras regulates SCF(β-TrCP) protein activity and specificity via its effector protein NORE1A. The Journal of biological chemistry 17 25217643
2013 New insights on the function of SCF ubiquitin E3 ligases in the lung. Cellular signalling 17 23680451
2011 Regulation of cell fate determination by Skp1-Cullin1-F-box (SCF) E3 ubiquitin ligases. The International journal of developmental biology 17 21710433

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