Editors' ChoiceProtein Stability

Protein Degradation Regulates Sonic Hedgehog Signals

Science's STKE  07 Feb 2006:
Vol. 2006, Issue 321, pp. tw51
DOI: 10.1126/stke.3212006tw51

Huntzicker et al. have discovered a new layer of regulation in the Sonic hedgehog signaling pathway, which is known to contribute to birth defects and cancer in humans. The Gli transcription factors are mediators of Sonic hedgehog-dependent changes in gene expression. The authors found that two destruction signals are present in the Gli1 protein that target it for destruction by the proteasome. A conserved sequence in Gli1 mediated interaction with the ubiquitin E3 ligase βTrCP1, and mutation of the sequence partially decreased destruction of the protein in cultured cells. The authors used mutagenesis to find another sequence that accounted for the remainder of the proteasome-dependent degradation of the protein. Tumor formation was increased in animals expressing Gli protein lacking these degradation signals. Thus the stability of the Gli proteins appears to be an important factor in Sonic hedgehog signaling and its contribution to tumorigenesis.

E. G. Huntzicker, I. S. Estay, H. Zhen, L. A. Lokteva, P. K. Jackson, A. E. Oro, Dual degradation signals control Gli protein stability and tumor formation. Genes Dev. 20, 276-281 (2006). [Abstract] [Full Text]