Abstract
Germline mutations at loci encoding the transcription factor Microphthalmia (Mi), the cytokine receptor c-Kit, or its ligand Steel factor (S1) result in strikingly similar defects in mast cell and melanocyte development. Here we describe a biochemical link between Kit signalling and the activity of Mi. Stimulation of melanoma cells with S1 results in activation of MAP kinase, which in turn phosphorylates Mi at a consensus target serine. This phosphorylation upregulates Mi transactivation of the tyrosinase pigmentation gene promoter. In addition to modulating pigment production, such signalling may regulate the expression of genes essential for melanocyte survival and development. The pathway represents a new application of the general MAP kinase machinery in transducing a signal between a tissue-specific receptor at the cell surface and a tissue-specific transcription factor in the nucleus.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Humans
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MAP Kinase Kinase Kinase 1*
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Melanocytes / metabolism*
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Microphthalmia-Associated Transcription Factor
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Mutagenesis, Site-Directed
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Phosphorylation
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Proto-Oncogene Proteins c-kit / metabolism*
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Serine / metabolism
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Signal Transduction*
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Transcription Factors*
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Tumor Cells, Cultured
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Flavonoids
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MITF protein, human
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Microphthalmia-Associated Transcription Factor
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Transcription Factors
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Serine
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Proto-Oncogene Proteins c-kit
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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MAP Kinase Kinase Kinase 1
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MAP3K1 protein, human
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one