Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-kit receptor tyrosine kinase belongs to the PDGF/CSF-1/c-kit receptor subfamily. The kit-ligand, KL, also called steel factor, is synthesized from two alternatively spliced mRNAs as transmembrane proteins that can either be proteolytically cleaved to produce soluble forms of KL or can function as cell-associated molecules. The c-kit receptor kinase and KL are encoded at the white spotting (W) and steel (Sl) loci of the mouse, respectively. Mutations at both the W and the Sl locus cause deficiencies in gametogenesis, melanogenesis and hematopoiesis. The c-kit receptor is expressed in the cellular targets of W and Sl mutations, while KL is expressed in their microenvironment. In melanogenesis, c-kit is expressed in melanoblasts from the time they leave the neural crest and expression continues during embryonic development and in the melanocytes of postnatal animals. In gametogenesis c-kit is expressed in primordial germ cells, in spermatogonia, and in primordial and growing oocytes, implying a role at three distinct stages of gametogenesis. Many mutant alleles are known at W and Sl loci and their phenotypes vary in the degree of severity in the different cellular targets of the mutations. While many W and Sl alleles severely affect primordial germ cells (PGC), several mild Sl alleles have weak effects on PGCs and exhibit differential male or female sterility. Steel Panda (Sl(pan)) is a KL expression mutation in which KL RNA transcript levels are reduced in most tissues analyzed. In female Sl(pan)/Sl(pan) mice, ovarian follicle development is arrested at the one layered cuboidal stage as a result of reduced KL expression in follicle cells, indicating a role for c-kit in oocyte growth. Wsh is a c-kit expression mutation, which affects mast cells and melanogenesis. While the mast cell defect results from lack of c-kit expression, the pigmentation deficiency appears to stem from ectopic c-kit receptor expression in the somitic dermatome at the time of migration of melanoblasts from the neural crest to the periphery. It is proposed that the ectopic c-kit expression in Wsh mice affects early melanogenesis in a dominant fashion. The "sash" or white belt of Wsh/+ animals and some other mutant mice is explained by the varying density of melanoblasts along the body axis of wild-type embryos.
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PMID:The kit-ligand (steel factor) and its receptor c-kit/W: pleiotropic roles in gametogenesis and melanogenesis. 751 81

Mechanisms affecting mast cell and melanocyte growth and function are still poorly understood. This report summarizes the current state of knowledge on a recently described growth factor for both these cell types and for primitive haematopoietic stem cells. Stem cell factor (SCF), also named mast cell growth factor or kit-ligand, has only recently been cloned and has been shown to be encoded on human chromosome 12. It may be of specific importance in cutaneous physiology and pathology since it is produced by several cell types in the skin (e.g. fibroblasts, keratinocytes, endothelial cells) and since it affects melanocyte and mast cell growth, survival, secretion and adhesion as well as migration into tissues. Defects in the genes encoding for the SCF receptor (c-kit-protein) have been shown to be responsible for human piebaldism. A pathogenetic role in mastocytosis has recently been proposed, but remains to be proven. SCF receptor expression is decreased on cells of some malignant cell lines compared to their physiological counterparts, making it unlikely that SCF is a key factor in malignant transformation and cellular hyperproliferation. In haematopoiesis, SCF acts primarily in concert with other growth factors, and we show here that alone in serum-free culture it has no effect on mast cell growth. Furthermore, there is evidence that besides SCF, additional mast cell growth factors are secreted by fibroblasts and keratinocytes, suggesting a complex orchestration of several growth factors in the regulation of cutaneous growth and differentiation in which SCF plays only one part.
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PMID:Stem cell factor, a novel cutaneous growth factor for mast cells and melanocytes. 753 33

Mast cell neutral proteases are the most precise markers of heterogeneity among human mast cells. Two types of human mast cells have been recognized. MCTC cells contain tryptase together with chymase, cathepsin-G like protease, and mast cell carboxypeptidase; MCT cells contain tryptase, but lack the other neutral proteases present in MCTC cells. All mast cells develop from hemopoietic stem cells. In vitro procedures for studying mast cell growth have been developed, using the major human mast cell growth factor, stem cell factor (SCF, also called Kit-ligand). Cultures of hemopoietic progenitor cells in the presence of SCF alone result in selective differentiation to mast cells. The same progenitor cells can be induced to differentiate into other lineages when SCF is used with various lineage-specific colony-stimulating factors such as erythropoietin for erythrocytes. Mast cell development from hematopoietic progenitors may represent a "default pathway," occurring optimally in a permissive microenvironment such as skin, bowel, and lung. The presence or absence of certain cytokines in blood and bone marrow may create a non-permissive environment, thus the absence of granulated mast cells in such locations.
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PMID:Human mast cell heterogeneity. 772 Oct 78

Mast cells are the principal initial effector cells in the modulation of allergic inflammation. They are now known to arise from CD34+ pluripotential stem cells, circulate through the blood as CD34+, Fc epsilon RI-, Kit+ committed but undifferentiated cells, and migrate into tissues where they mature in the presence of Kit-ligand (stem cell factor) and other locally produced cytokines. Mast cells undergo programmed cell death (apoptosis) when stem cell factor is not available. Mast cells adhere to specific connective tissue components such as fibronectin and laminin. This interaction localizes mast cells to specific sites while altering their biologic responsiveness. Mast cells, when activated through Fc epsilon RI, release and generate a wide variety of cytokines including IL-4 and IL-5. This information provides new insights on how allergic reactions may be modified by developing strategies to effect mast cell viability, survival and localization; and the production of inflammatory mediators.
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PMID:Contemporary issues in mast cell biology. 893 94

Membrane growth factors that are processed to produce soluble ligands may function both as soluble factors and as membrane factors. The membrane growth factor Kit-ligand (KL), the ligand of the Kit receptor tyrosine kinase, is encoded at the Sl locus, and mice carrying Sl mutations have defects in hematopoiesis, gametogenesis, and melanogenesis. Two alternatively spliced KL transcripts encode two cell-associated KL protein products, KL-1 and KL-2. The KL-2 protein lacks the major proteolytic cleavage site for the generation of soluble KL, thus representing a more stable cell-associated form of KL. We investigated the consequences of exclusive expression of KL-2 in vivo. The KL gene in embryonic stem cells was modified and KL exon 6 was replaced with a PGKneoNTRtkpA cassette by homologous recombination, and mice carrying the SlKL2 allele were obtained. SlKL2/SlKL2 mice had only slightly reduced levels of soluble KL in their serum, suggesting that in vivo KL-2 may be processed to produce soluble KL-2S. The steady-state characteristics of the hematopoietic system and progenitor numbers were normal, and the mutant animals were not anemic. However, mast cell numbers in the skin and peritoneum were reduced and the mutant animals displayed increased sensitivity to sublethal doses of gamma-irradiation. Therefore, KL-2 may substitute for KL-1 in most situations with the exception of the production of mast cells, and induced proteolytic cleavage of KL-1 to produce soluble KL may have a role in the regeneration of hematopoietic tissue after radiation injury.
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PMID:Consequences of exclusive expression in vivo of Kit-ligand lacking the major proteolytic cleavage site. 975 63

It has been established that mast cells can alter their expression of granule chymases and tryptases in vivo. In vitro, a reversible cytokine regulation has so far only been demonstrated for chymases. We now show a reversible and cytokine-regulated expression of the tryptases MMCP-6 and MMCP-7 and of the chymases MMCP-1, MMCP-2 and MMCP-4 in the continuous murine mast cell line L138.8A. The L138.8A mast cells lacked expression of mRNA for mast cell-specific proteases when cultured in IL-3, and only 49% and 41% of the cells were c-kit+ and FcepsilonRI+, respectively, by flow cytometry. Kit-ligand/stem cell factor induced synthesis of the chymase MMCP-4 and the tryptases MMCP-6 and MMCP-7 and increased the fraction of c-kit+ and FcepsilonRI+ L138.8A cells to >70%. Kit-ligand-induced tryptase expression was suppressed in the presence of IL-3 or IL-9, and reversed after withdrawal of kit-ligand. IL-9 or IL-3/IL-10 promoted the formation of Alcian blue+ granules and increased the fraction of c-kit+ and FcepsilonRI+ L138.8A cells to >90%. IL-9 further induced the expression of the chymases MMCP-1, MMCP-2 and MMCP-4. Thus, the immature mast cell line L138.8A has the capacity to modulate both tryptase and chymase expression and represents the first model system to analyze the molecular regulation of tryptase expression in vitro.
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PMID:Reversible expression of tryptases in continuous L138.8A mast cells. 1106 78

Mast cells accumulate in tissues undergoing angiogenesis during tumor growth, wound healing, and tissue repair. Mast cells can secrete angiogenic factors such as vascular endothelial growth factor (VEGF). Ionizing irradiation has also been shown to have angiogenic potential in malignant and nonmalignant diseases. We observed that low-dose irradiation fosters mast cell-dependent vascular regeneration in a limb ischemia model. Irradiation promoted VEGF production by mast cells in a matrix metalloproteinase-9 (MMP-9)-dependent manner. Irradiation, through MMP-9 up-regulated by VEGF in stromal and endothelial cells, induced the release of Kit-ligand (KitL). Irradiation-induced VEGF promoted migration of mast cells from the bone marrow to the ischemic site. Irradiation-mediated release of KitL and VEGF was impaired in MMP-9-deficient mice, resulting in a reduced number of tissue mast cells and delayed vessel formation in the ischemic limb. Irradiation-induced vasculogenesis was abrogated in mice deficient in mast cells (steel mutant, Sl/Sl(d) mice) and in mice in which the VEGF pathway was blocked. Irradiation did not induce progenitor mobilization in Sl/Sl(d) mice. We conclude that increased recruitment and activation of mast cells following irradiation alters the ischemic microenvironment and promotes vascular regeneration in an ischemia model. These data show a novel mechanism of neovascularization and suggest that low-dose irradiation may be used for therapeutic angiogenesis to augment vasculogenesis in ischemic tissues.
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PMID:Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization. 1615 86

The intricately regulated Ras pathway coordinates multiple kit-ligand-induced mast cell functions, including chemotaxis, proliferation, and degranulation. However, the intracellular proteins that modulate the intensity and duration of stem cell factor-induced signals and the consequent cellular response are incompletely understood. Scaffolding proteins coordinate the spatial organization of mitogen-activated protein kinase proteins that may potentiate and/or inhibit cell functions. The kinase suppressor of Ras (KSR1) protein is known to function as a molecular scaffold and coordinates the organization of Raf/Mek/Erk in response to receptor tyrosine kinases. However, the impact of KSR1 in myeloid mast cell functions and in response to stem cell factor remains unknown. In the present study, we investigated the role of KSR1 in regulating cellular functions of bone marrow-derived mast cells of KSR1-deficient ((-/-)) mice. Genetic disruption of KSR1 resulted in both striking reductions in kit-ligand-mediated proliferation and degranulation, which are commonly attributed to mitogen-activated protein kinase signals. Surprisingly, disruption of the KSR1 scaffold also resulted in a decline in migration that is generally not linked to Raf-Erk signals. We found that loss of KSR1 does impact the biochemical activation of p21-activated kinase, a kinase that is known to modulate Raf-Erk signals and also F-actin polymerization key to mast cell migration. Collectively, these studies demonstrate that the scaffolding protein KSR1 has an important role in multiple kit-ligand-mediated mast cell functions. This study elucidates varied mast cell physiological functions for KSR1, including those related to cytoskeletal organization, and it suggests a novel molecular target for attenuating mast cell-mediated inflammation.
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PMID:Kinase suppressor of Ras (KSR1) modulates multiple kit-ligand-dependent mast cell functions. 2172 14