KITLG encodes Kit ligand (stem cell factor, SCF; also known as mast cell growth factor/MGF and Steel factor), the sole physiological ligand for the class III receptor tyrosine kinase KIT (CD117). It is a four-helix-bundle cytokine of the SCF family, synthesized as a single-pass type I transmembrane precursor that can either remain membrane-anchored to support juxtacrine signaling or be released as a soluble ectodomain (sKITLG) by regulated proteolytic shedding; alternative splicing of the protease-sensitive exon-6 region tunes the balance between the readily shed (SCF248) and predominantly membrane-bound (SCF220) forms. Biologically active as a non-covalent homodimer, KITLG binds two KIT ectodomains and brings the receptors together, driving KIT dimerization and trans-autophosphorylation and thereby activating PI3K-AKT, RAS-RAF-MAPK, PLCgamma and STAT signaling in the receiving cell. Through this receptor engagement KITLG functions as an essential niche and growth-factor signal controlling the survival, proliferation, migration and differentiation of KIT-expressing cells, including hematopoietic stem and progenitor cells, mast cells, melanocytes and germ cells. It is produced by supporting cells such as bone-marrow stromal and perivascular cells, keratinocytes, endothelial cells and gonadal Sertoli cells. Consistent with these roles, KITLG variants cause familial progressive hyperpigmentation, non-syndromic unilateral or asymmetric deafness and Waardenburg syndrome type 2F, and common variation at the locus underlies normal skin, hair and eye pigmentation variation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001541 ovarian follicle development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic ortholog-transfer annotation (from rat Kitlg P21581) placing KITLG in ovarian follicle development. KIT/KITL signaling supports oocyte and follicle survival, so this reproductive developmental role is biologically plausible, but it is a downstream, tissue-specific consequence of KITLG's receptor-binding activity rather than a core molecular function. Reason: Consistent with KITLG's established role as a germ-cell/gonadal niche cytokine, but the annotation is electronic and reflects a pleiotropic developmental process; keep as a non-core process annotation. |
| GO:0003006 developmental process involved in reproduction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Broad ARBA machine-learning annotation. KITLG does contribute to reproduction (germ cell survival/migration in testis and ovary), but this term is very general and captures a pleiotropic developmental role rather than the core function. Reason: Not incorrect, but a general electronic term; retained as a non-core developmental process annotation. |
| GO:0005125 cytokine activity | IEA GO_REF:0000107 | ACCEPT | Summary: SCF is a bona fide hematopoietic cytokine/growth factor: it augments proliferation of myeloid and lymphoid progenitors and synergizes with colony-stimulating factors. This is a core molecular function of KITLG. Reason: Well supported; SCF is a classic four-helix-bundle cytokine that acts as a receptor ligand/growth factor. Core molecular function. Supporting Evidence: PMID:2208279 SCF is able to augment the proliferation of both myeloid and lymphoid hematopoietic progenitors in bone marrow cultures. SCF exhibits potent synergistic activities in conjunction with colony-stimulating factors |
| GO:0005173 stem cell factor receptor binding | IEA GO_REF:0000120 | ACCEPT | Summary: KITLG is the defining ligand for the KIT receptor; stem cell factor receptor binding is its central, defining molecular function. Supported electronically here and by structural and functional data (KIT dimerization driven by SCF binding). Reason: This is the core molecular function of KITLG. Multiple independent lines of evidence (structural, functional expression) confirm KIT binding. Supporting Evidence: PMID:17662946 The structures show that KIT dimerization is driven by SCF binding whose sole role is to bring two KIT molecules together. |
| GO:0005173 stem cell factor receptor binding | TAS PMID:2208279 Primary structure and functional expression of rat and human... | ACCEPT | Summary: TAS annotation from the original SCF cloning/functional-expression paper. Recombinant human SCF was shown to be biologically active on hematopoietic progenitors via KIT, confirming stem cell factor receptor binding. Reason: Core molecular function, supported by the primary functional-expression study. Supporting Evidence: PMID:2208279 truncated forms of the rat and human proteins have been expressed in E. coli and mammalian cells and have been shown to possess biological activity |
| GO:0005515 protein binding | IPI PMID:17662946 Structural basis for activation of the receptor tyrosine kin... | MODIFY | Summary: IPI annotation recording a physical interaction with KIT (UniProtKB:P10721). The cited crystallographic study establishes that SCF binds and dimerizes KIT. The generic "protein binding" term is uninformative, but the interactant and the paper identify a specific, more informative molecular function. Reason: The interaction partner is KIT and the supporting paper defines the binding as the SCF/KIT ligand-receptor interaction; replace the uninformative generic term with the specific stem cell factor receptor binding function per curation policy. Proposed replacements: stem cell factor receptor binding Supporting Evidence: PMID:17662946 The structures show that KIT dimerization is driven by SCF binding whose sole role is to bring two KIT molecules together. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: The soluble form of KITLG (sKITLG) is generated by proteolytic shedding of the extracellular domain and is secreted; extracellular region is therefore a genuine functional location for the soluble ligand. Reason: Consistent with the secreted soluble KIT ligand form documented in UniProt. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433374 | ACCEPT | Summary: Reactome-derived location for the soluble/secreted SCF form participating in SCF-KIT signaling reactions. Correct location for sKITLG. Reason: Secreted soluble SCF acts in the extracellular region; consistent with the biology. One of many redundant Reactome location annotations, all correct. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433395 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433418 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433428 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433451 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433454 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433456 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433471 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433488 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433501 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433506 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433514 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1433542 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1470009 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1470010 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1470012 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1472121 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1562640 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-1562641 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-205231 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-205234 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-205238 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-205244 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-205262 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-205286 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-205289 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-205306 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-205319 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-205321 | ACCEPT | Summary: Reactome reaction "Interaction of KIT and sSCF" locates the soluble SCF in the extracellular region where it engages KIT; correct for sKITLG. Reason: Correct location for the soluble ligand; redundant with other extracellular-region annotations. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-205328 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2316434 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2400009 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5672965 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9669893 | ACCEPT | Summary: Reactome location annotation for secreted soluble SCF; correct for sKITLG. Reason: Redundant with other extracellular-region annotations; correct location for the soluble ligand. |
| GO:0005737 cytoplasm | IDA PMID:26522471 Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymm... | ACCEPT | Summary: Immunofluorescence of FLAG-tagged transmembrane KITLG in transfected cells directly detected KITLG in the cytoplasm (as well as at the cell membrane and in cell projections). This reflects the transmembrane precursor in transit through the secretory pathway. Reason: Directly observed localization; correct for the transmembrane form. Non-core relative to the extracellular signaling function. Supporting Evidence: PMID:26522471 Both FLAG-tagged wild-type and p.Leu104Val KITLG were detected in the cytoplasm and at the cell membrane, as well as in lamellipodia and filipodia |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation from the UniProt subcellular-location keyword, consistent with the IDA cytoplasmic localization of the transmembrane precursor. Reason: Redundant with the IDA cytoplasm annotation; consistent with the biology. |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic annotation derived from the "Cytoplasm, cytoskeleton" subcellular-location keyword (assigned by similarity in UniProt). KITLG is a secreted/membrane cytokine ligand; a cytoskeletal association is not a functional site of action and rests only on a by-similarity keyword. Reason: Weakly supported (by-similarity subcellular keyword only) and not a functional location for a cytokine ligand; retain as non-core rather than treating as a core location. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBD/IBA) annotation placing KITLG as active at the plasma membrane at ancestral node PTN002611905. Membrane-bound SCF signals to KIT from the plasma membrane (juxtacrine), so is_active_in plasma membrane is appropriate. KITLG's own appearance in the WITH/FROM list reflects experimental grounding on the target. Reason: Sound node placement; membrane-anchored SCF is functionally active at the plasma membrane. Core functional location for the membrane-bound form. |
| GO:0005886 plasma membrane | IDA PMID:26522471 Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymm... | ACCEPT | Summary: Immunofluorescence directly localized transmembrane KITLG to the cell membrane; a DCUA variant (p.His67_Cys68delinsArg) that fails to reach the membrane is pathogenic, underscoring the functional importance of this location. Reason: Directly observed; core functional location of the membrane-bound ligand. Supporting Evidence: PMID:26522471 Both FLAG-tagged wild-type and p.Leu104Val KITLG were detected in the cytoplasm and at the cell membrane, as well as in lamellipodia and filipodia |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation consistent with the single-pass type I plasma-membrane topology of KITLG. Reason: Redundant with IDA/IBA plasma-membrane annotations; correct. |
| GO:0005886 plasma membrane | NAS PMID:10049787 Parathyroid hormone-regulated production of stem cell factor... | ACCEPT | Summary: Osteoblasts express the exon-6-omitted, membrane-associated SCF isoform, supporting plasma-membrane localization of KITLG. Reason: Consistent with membrane-anchored SCF; correct location. Supporting Evidence: PMID:10049787 mRNAs without exon 6 produce membrane-associated SCF isoforms in rodents, suggesting that human SCFs are processed similarly |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1433374 | ACCEPT | Summary: Reactome "Processing of SCF isoform 1" places membrane SCF at the plasma membrane prior to shedding; correct location for the transmembrane precursor. Reason: Redundant with other plasma-membrane annotations; correct. |
| GO:0007155 cell adhesion | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping from the SCF domain (IPR003452). Membrane-bound SCF can promote adhesion/retention of KIT-expressing cells at cell-cell contacts, so the term is not unreasonable, but the mapping is broad and cell adhesion is a secondary consequence of juxtacrine ligand presentation rather than a core function. Reason: Plausible for the membrane form but derived from a broad domain-to-GO mapping and peripheral to KITLG's core receptor-binding function; retain as non-core. |
| GO:0007165 signal transduction | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Inter-ontology inference from cytokine activity. KITLG initiates signal transduction by engaging KIT, so involvement is correct, but the term is very general. Reason: Correct but generic; the specific role is receptor binding/receptor activation, so keep this broad process term as non-core. |
| GO:0008284 positive regulation of cell population proliferation | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic annotation (node PTN002611905) that KITLG positively regulates cell proliferation. SCF is a mitogenic growth factor for KIT-expressing cells (hematopoietic progenitors, mast cells, melanocytes, germ cells). Node placement is sound and KITLG's own presence in WITH/FROM reflects experimental grounding. Reason: Core process: KITLG drives proliferation of KIT+ target cells. Well supported across the family and by primary data. Supporting Evidence: PMID:2208279 SCF is able to augment the proliferation of both myeloid and lymphoid hematopoietic progenitors in bone marrow cultures |
| GO:0008284 positive regulation of cell population proliferation | IDA PMID:9722506 Insulin-like growth factor-I augments erythropoietin-induced... | ACCEPT | Summary: Experimental (IDA) annotation to positive regulation of cell proliferation. The cached abstract foregrounds IGF-I/EPO/STAT5 in the SCF-responsive F-36P cell line; the curator read the full text, and promotion of proliferation is a well-established KITLG function, so the annotation is retained. Reason: Consistent with KITLG's core growth-factor role; per curation policy an experimental annotation is not removed merely because the cached abstract emphasizes another factor. Defer to the curator's full-text reading. |
| GO:0008284 positive regulation of cell population proliferation | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation consistent with SCF's mitogenic growth-factor activity. Reason: Redundant with IBA/IDA positive-regulation-of-proliferation annotations; correct. |
| GO:0008584 male gonad development | IEP PMID:17848411 Developmental changes in human fetal testicular cell numbers... | KEEP AS NON CORE | Summary: IEP (expression-pattern) annotation: KITL (KITLG) is a Sertoli-cell transcript in the human fetal testis whose expression rises through the second trimester, consistent with a role in male gonad development. This is a tissue-specific developmental role inferred from expression. Reason: Supported by expression data and consistent with the germ-cell niche role, but a developmental, tissue-specific process rather than KITLG's core molecular function. Supporting Evidence: PMID:17848411 Transcripts encoding Sertoli (KITL, FGF9, SOX9, FSHR, WT1) |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: General membrane location; KITLG is a single-pass membrane protein, so this is correct but less informative than the plasma membrane annotations. Reason: Correct but a general parent term; the more specific plasma membrane annotation is the informative one. Acceptable as a broad IEA location. |
| GO:0030027 lamellipodium | IDA PMID:26522471 Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymm... | ACCEPT | Summary: Immunofluorescence directly localized transmembrane KITLG to lamellipodia in transfected cells, alongside cell membrane and cytoplasm. Reason: Directly observed cell-projection localization; non-core. Supporting Evidence: PMID:26522471 Both FLAG-tagged wild-type and p.Leu104Val KITLG were detected in the cytoplasm and at the cell membrane, as well as in lamellipodia and filipodia |
| GO:0030027 lamellipodium | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic subcellular-keyword annotation consistent with the IDA lamellipodium localization. Reason: Redundant with the IDA lamellipodium annotation; correct. |
| GO:0030175 filopodium | IDA PMID:26522471 Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymm... | ACCEPT | Summary: Immunofluorescence directly localized transmembrane KITLG to filopodia in transfected cells, alongside cell membrane and cytoplasm. Reason: Directly observed cell-projection localization; non-core. Supporting Evidence: PMID:26522471 Both FLAG-tagged wild-type and p.Leu104Val KITLG were detected in the cytoplasm and at the cell membrane, as well as in lamellipodia and filipodia |
| GO:0030175 filopodium | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic subcellular-keyword annotation consistent with the IDA filopodium localization. Reason: Redundant with the IDA filopodium annotation; correct. |
| GO:0035162 embryonic hemopoiesis | IDA PMID:21149635 Monocytic cells derived from human embryonic stem cells and ... | KEEP AS NON CORE | Summary: Experimental (IDA, DFLAT) annotation to embryonic hemopoiesis. SCF is a core niche cytokine for KIT+ hematopoietic stem/progenitor cells and is used in fetal-liver/hESC hematopoietic differentiation. Being a required cytokine signal, KITLG participates in hemopoiesis via its receptor-binding/cytokine activity. This is a developmental process, non-core relative to the molecular function. Reason: Consistent with KITLG's established hematopoietic niche role; retained as a non-core developmental process. Not removed, as it is an experimental annotation and the role is well established. |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Very broad ARBA electronic term. KITLG contributes to development of several organs/tissues (gonad, inner ear melanocytes, hematopoietic system), but this term is too general to convey specific function. Reason: Correct but very general electronic annotation; retain as non-core. |
| GO:1901534 positive regulation of hematopoietic progenitor cell differentiation | TAS PMID:2208279 Primary structure and functional expression of rat and human... | ACCEPT | Summary: TAS from the primary SCF paper: SCF augments proliferation of myeloid and lymphoid progenitors and synergizes with colony-stimulating factors to increase colony numbers and size, consistent with positive regulation of hematopoietic progenitor differentiation. This is a central biological role of KITLG. Reason: Well supported core hematopoietic role; KITLG is a key regulator of progenitor expansion/differentiation. Supporting Evidence: PMID:2208279 SCF exhibits potent synergistic activities in conjunction with colony-stimulating factors, resulting in increased colony numbers and colony size |
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