Mechanism of kit ligand, phorbol ester, and calcium-induced down-regulation of c-kit receptors in mast cells

The proto-oncogene c-kit is allelic with the white spotting locus (W) on mouse chromosome 5 and it encodes a transmembrane protein tyrosine kinase which belongs to the platelet-derived growth factor and macrophage-colony stimulating factor (CSF-1) receptor subfamily. In an effort to study the functi...

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Bibliographic Details
Published in:The Journal of biological chemistry 1993-07, Vol.268 (19), p.14189-14201
Main Authors: YEE, N. S, LANGEN, H, BESMER, P
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Autoradiography
Biological and medical sciences
Calcium - metabolism
Cell receptors
Cell structures and functions
Cells, Cultured
Dose-Response Relationship, Drug
Down-Regulation
Electrophoresis, Polyacrylamide Gel
Fundamental and applied biological sciences. Psychology
Hematopoietic Cell Growth Factors - isolation & purification
Hematopoietic Cell Growth Factors - pharmacology
Ionomycin - pharmacology
Kinetics
Mast Cells - drug effects
Mast Cells - metabolism
Methionine - metabolism
Mice
Mice, Inbred C57BL
Miscellaneous
Molecular and cellular biology
Molecular Weight
Proto-Oncogene Proteins - biosynthesis
Proto-Oncogene Proteins - drug effects
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-kit
Receptors, Cell Surface - biosynthesis
Receptors, Cell Surface - drug effects
Receptors, Cell Surface - metabolism
Recombinant Proteins - pharmacology
Stem Cell Factor
Sulfur Radioisotopes
Tetradecanoylphorbol Acetate - pharmacology
Time Factors
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Summary:The proto-oncogene c-kit is allelic with the white spotting locus (W) on mouse chromosome 5 and it encodes a transmembrane protein tyrosine kinase which belongs to the platelet-derived growth factor and macrophage-colony stimulating factor (CSF-1) receptor subfamily. In an effort to study the function of the c-kit receptor, specifically the physiological mechanism of controlling the signal induced by the ligand, the effect and mechanism of down-regulation of the c-kit receptor by the kit ligand (KL) was investigated in mast cells. Following preincubation with KL, the capacity of mast cells to bind kit antibody was reduced and binding of radiolabeled KL to mast cells decreased with similar kinetics, suggesting that KL stimulates the loss of c-kit receptor from the cell surface. After binding to the c-kit receptor, KL was rapidly internalized, and degradation of the receptor was accelerated. The c-kit receptor was transmodulated by the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA) and by the calcium ionophore ionomycin. TPA- and ionomycin-induced down-regulation of the c-kit receptor was accompanied by release of the extracellular domain of the receptor, presumably by proteolytic cleavage near the transmembrane domain. Release of the extracellular domain of the c-kit receptor occurred also in untreated cells but at a slow rate. In addition, ionomycin induced shedding of the intact c-kit receptor. In mast cells depleted of protein kinase C, the c-kit receptor remained sensitive to down-regulation induced by KL and ionomycin, but not by treatment with TPA. Therefore, the down-regulation of the c-kit receptor induced by KL, activated protein kinase C, and an increased level of intracellular calcium is mediated through independent mechanisms.
ISSN:0021-9258
1083-351X
DOI:10.1016/s0021-9258(19)85226-2