MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes

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Abstract

Germline mutations at loci encoding the transcription factor Microphthalmia (Mi), the cytokine receptor c-Kit, or its ligand Steel factor (Sl) result in strikingly similar defects in mast cell and melanocyte development1,2,3. Here we describe a biochemical link between Kit signalling and the activity of Mi. Stimulation of melanoma cells with Sl 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.

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Figure 1: Kit-induced Mi phosphorylation.
Figure 2: Serine phosphorylation of Mi is prevented by MEK inhibition.
Figure 3: Mi phosphorylation at S73 by MAPK.
Figure 4: MAPK phosphorylation enhances Mi-dependent transactivation.

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Acknowledgements

We thank J. Jackson and J. Abraham for technical help, S. Galli, G. Cooper, M.Greenberg, B. Neel, D. Ron and P. Sharp for discussion, R. Halaban for 501mel cells, and members of the Burakoff laboratory for advice and assistance. This work was supported by grants from the NIH, the Pew Foundation, and the James S. McDonnell Foundation. T.J.H. is a Medical Foundation Fellow; D.E.F. is Nirenberg Fellow.

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Correspondence to David E. Fisher.

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