Coupling Activation and Degradation

Science's STKE  22 Feb 2000:
Vol. 2000, Issue 20, pp. tw5
DOI: 10.1126/stke.2000.20.tw5

Microphthalmia (Mi) is a transcription factor essential for melanocyte development and function. Wu et al. demonstrate that Mi is activated and targeted for proteasome-mediated degradation by phosphorylation following stimulation of receptor tyrosine kinase c-Kit and activation of the mitogen-activated protein kinase (MAPK) pathway. Mi was phosphorylated on two residues, serine 73 and serine 409, by MAPK and Rsk-1, respectively. Mutation of either serine individually did not prevent proteasome-mediated degradation, although functional activity was reduced. Mutation of both residues resulted in a stable protein that was functionally inactive, yet retained DNA binding capability. Thus, dual phosphorylation of Mi leads to both its activation and degradation following stimulation of the MAPK pathway.

Wu, M., Hemesath, T.J., Takemoto, C.M., Horstmann, M.A., Wells, A.G., Price, E.R., Fisher, D.Z., and Fisher, D.E. (2000) c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanaocyte factor Mi. Genes Dev. 14: 301-312. [Abstract] [Full Text]