Disease relevance of KITLG

• In skin samples containing lesions and in clinically normal skin from patients with mastocytosis, however, mast-cell growth factor was also found free in the dermis and in the extracellular spaces between keratinocytes, suggesting the presence of a soluble form of this protein [1].
• The altered distribution of mast-cell growth factor in the skin of patients with cutaneous mastocytosis is consistent with abnormal production of the soluble form of this factor [1].
• The demonstration that r-hSCF can promote both the hyperplasia and the functional activation of human mast cells and melanocytes in vivo has implications for our understanding of the role of endogenous SCF in health and disease [2].
• Five subjects developed areas of persistent hyperpigmentation at r-hSCF injection sites; by light microscopy, these sites exhibited markedly increased epidermal melanization and increased numbers of melanocytes [2].
• In this study we tested the mitogenic activity of recombinant human SCF on myeloid leukemia cells as well as the expression of its receptor [3].

Psychiatry related information on KITLG

• The factors regulating this release may include histamine-releasing factors, interleukin-3, the c-kit ligand, the cyclic nucleotide system, psychological factors, metabolites of arachidonic acid and cytokines [4].
• The discovery of MGF and muscle IGF-1 provides a link between physical activity and gene expression [5].

High impact information on KITLG

• After phosphorylation, the IKK phosphoacceptor sites on IkappaB serve as an essential part of a specific recognition site for E3RS(IkappaB/beta-TrCP), an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IkappaB ubiquitination and degradation [6].
• Finally, components of both the APC and the SCF E3 ubiquitin-ligase complex contain several conserved sequence motifs, including WD-40 repeats and cullin homology domains, which suggest that both complexes may use a similar mechanism for substrate ubiquitination [7].
• Mechanism of lysine 48-linked ubiquitin-chain synthesis by the cullin-RING ubiquitin-ligase complex SCF-Cdc34 [8].
• This finding has profound implications for understanding plant physiology and development and for defining new modes of regulation of SCF ubiquitin ligase complexes [9].
• In this issue of Cell, Deffenbaugh et al. provide experimental support for a model in which the dynamic release of the ubiquitin-charged E2 Cdc34 from its primary binding site within the rigid cradle-like SCF E3 complex allows for unexpected spatial flexibility to assemble a polyubiquitin chain [10].

Chemical compound and disease context of KITLG

• c-kit ligand stimulates tyrosine phosphorylation of a similar pattern of phosphotyrosyl proteins in primary primitive normal hematopoietic progenitors that are constitutively phosphorylated in comparable primitive progenitors in chronic phase chronic myelogenous leukemia [11].
• In addition, this form of SCF induced the expression of a pertussis toxin-sensitive G(i) protein, G(i3) that interacts with MBP to trigger mast cell non-IgE-dependent activation in a manner similar to other cationic compounds such as compound 48/80 [12].
• Mast cells, identified by tryptase and chymase immunostaining on consecutive tissue sections, showed immunoreactivity for SCF and c-kit in both normal and cancerous specimens and their number was significantly increased (p = 0.03) in pancreatic cancer compared with the normal pancreas [13].
• A detailed study of the involvement of SCF and its receptor c-kit in normal erythropoiesis will help elucidate intrinsic irregularities of anemias such as Diamond Blackfan Anemia, an aregenerative congenital anemia [14].
• Several lines of evidence have previously reported that KIT and its ligand stem cell factor (SCF) have a regulatory role in melanocyte development and survival, suggesting a rational mechanism of action for imatinib mesylate in the pathogenesis of hypopigmentation [15].

Biological context of KITLG

• Stem cell factor (SCF), a key regulator of hematopoiesis, potently synergizes with a number of hematopoietic growth factors [16].
• On the basis of these observations, a model for SCF small middle dotc-kit complex formation and dimerization is proposed [17].
• In unilineage erythropoietic culture of CD34+ progenitors, short-term pretreatment of immature erythroid precursors with SCF results in protection from apoptosis induced by chemotherapeutic agents and restores normal proliferation and differentiation after removal of the cytotoxic stimulus [18].
• Moreover, IL-9 acts synergistically with SCF for recruiting quiescent leukemic cells in cell cycle [19].
• Among the 12 erythroid growth-promoting cytokines tested, stem cell factor (SCF) at a concentration of 50 ng/mL resulted in the most significant increase in cell proliferation and HbF content [20].

Anatomical context of KITLG

• A wheal and flare reaction developed at each r-hSCF injection site; by electron microscopy, most dermal mast cells at these sites exhibited extensive, anaphylactic-type degranulation [2].
• We analyzed the effects of recombinant human SCF (r-hSCF, 5-50 micrograms/kg/day, injected subcutaneously) on mast cells and melanocytes in a phase I study of 10 patients with advanced breast carcinoma [2].
• Stem cell factor (SCF) plays important roles in hematopoiesis and the survival, proliferation, and differentiation of mast cells, melanocytes, and germ cells [17].
• Effects of the stem cell factor, c-kit ligand, on human megakaryocytic cells [21].
• Thus, the MB-02 cell line may be a useful model in which to investigate the molecular mechanisms of SCF action [22].

Associations of KITLG with chemical compounds

• A 14-d course of r-hSCF significantly increased dermal mast cell density at sites distant to those injected with the cytokine and also increased both urinary levels of the major histamine metabolite, methyl-histamine, and serum levels of mast cell alpha-tryptase [2].
• SCF mediates its biological effects by binding to and activating a receptor tyrosine kinase designated c-kit or SCF receptor [17].
• In the presence of SCF, the number of ECFC was greatly expanded during this culture period, and total production of benzidine-positive cells plus hemoglobin synthesis were ultimately increased [23].
• The ability of SCF to induce c-kit receptor dimerization was assessed by flow cytometric analysis of FRET between the donor fluorochrome FITC and the acceptor fluorochrome Cy3 [24].
• This costimulatory effect of SCF was not mediated by increased STAT5 tyrosine or serine phosphorylation or increased STAT5 DNA binding [25].

Physical interactions of KITLG

• CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex [26].
• Simultaneous addition of SCF and Kit-X to these cells resulted in a stoichiometric inhibition of SCF binding and a consequent decrease in autophosphorylation of the SCF receptor on tyrosine residues [27].
• SCF interacted with a number of hematopoietic growth factors to stimulate colony growth and was particularly effective in stimulating the formation of mixed-cell colonies from CD34+ soybean agglutinin negative (SBA-) cells [28].
• It is expressed by the primitive CD34 positive haemopoietic stem cells and interacts with the Kit ligand for signal transduction [29].
• Discrete protein interactions with the Grb2/c-Cbl complex in SCF- and TPO-mediated myeloid cell proliferation [30].

Enzymatic interactions of KITLG

• In addition, Btk is phosphorylated by SCF, which causes association of Btk with TRAIL-receptor1 [31].
• SCF alone tyrosine-phosphorylated several bands including the 145 kDa subunit of c-kit [32].

Co-localisations of KITLG

• In the intact fetal pancreas, SCF and c-Kit were observed co-localizing with cytokeratin 19 in both ductal and newly forming islet cells [33].

Regulatory relationships of KITLG

• UT-7 cultured with SCF and UT-7scf9 cultured without cytokines expressed GM-CSF, and anti-GM-CSF neutralizing antibody partially inhibited their growth [34].
• The ligand for flt-3 (FLT3L) exhibits striking structural homology with stem cell factor (SCF) and monocyte colony-stimulating factor (M-CSF) and also acts in synergy with a range of other hematopoietic growth factors (HGF) [35].
• The c-kit ligand stem cell factor and anti-IgE promote expression of monocyte chemoattractant protein-1 in human lung mast cells [36].
• SCF activated the human EPO receptor promoter and induced EPO receptor gene expression [37].
• Stem cell factor (c-kit ligand) enhances the interleukin-9-dependent proliferation of human CD34+ and CD34+CD33-DR- cells [38].

Other interactions of KITLG

• This study was designed to examine interactions between TNF-alpha and SCF [16].
• Recombinant human stem cell factor (SCF) is homologous with recombinant rat SCF (rrSCF) and is a ligand for c-kit [39].
• The kit ligand (KL), also termed stem cell factor (SCF), is a recently discovered hematopoietic growth factor that augments response of early progenitor cells to other growth factors and supports proliferation of continuous mast cell lines [21].
• Thus, highly homogenous populations of SCF/Epo-dependent erythroid progenitors can be obtained in large cell numbers that are most suitable for further biochemical and molecular studies [40].
• FL and SCF were equally effective in stimulating colony formation in combination with IL-3 [41].

Analytical, diagnostic and therapeutic context of KITLG

• Confocal microscopy showed redistribution of the c-kit receptor (from a diffuse distribution on the cell surface to "caps" at one end of the cell) within 3 minutes after SCF addition, followed by receptor internalization [24].
• RT-PCR analysis of cytokine and growth factor mRNA in MSCs and MDSCs revealed a very similar pattern of mRNAs including IL-6, -7, -8, -11, -12, -14, and -15, M-CSF, Flt-3 ligand, and SCF [42].
• Intradermal injections of SCF at 0.7 or 2.0 mug significantly increased skin pigmentation when compared to vehicle control [43].
• Using magnetic or fluorescence-activated cell sorting, SCF-ligating BMHC were enriched for pluripotent progenitor cells [44].
• Binding studies with BMHC demonstrated ligation of SCF to 4-11% of BMHC [44].

References