GSK3 Inhibits Hedgehog Signals

Science's STKE  09 Apr 2002:
Vol. 2002, Issue 127, pp. tw135
DOI: 10.1126/stke.2002.127.tw135

Glycogen synthase kinase 3 (GSK3) would have to be a contender for the "most-studied molecule" award. Once the subject of intense investigation for its role in control of metabolism, it is now recognized to have critical roles in the Wnt signaling pathway and diverse cellular processes, including development and tumorigenesis (see the Wnt Connections Map Pathway). Now, Jia et al. add a new role for the kinase in control of development. They find that GSK3 inhibits signaling through the Hedgehog pathway in Drosophila. Hedgehog is a secreted protein that acts in patterning during development, and disrupted Hh signaling appears to contribute to human diseases, including cancer. Hh signaling promotes processing of the transcription factor Ci (Cubitus interruptus) to a form that activates target promoters. Such processing of Ci is regulated by phosphorylation, and Jia et al.'s results indicate that Ci, once primed by phosphorylation by protein kinase A, is phosphorylated by GSK3 and that full phosphorylation is required for processing. Lack of the Drosophila GSK3 gene causes developmental abnormalities similar to those seen with excessive Hh signaling. Clearly, GSK3 is engaged in many signaling pathways, and unwanted cross talk seems to be prevented by localization of GSK3 in protein complexes with its signaling partners. Nevertheless, the authors note that their findings raise the possibility of coordinate regulation of both the Hh and Wnt pathways--two major regulatory pathways controlling development--through GSK3.

R. T. Moon, Wnt/beta-catenin pathway. Science's STKE (Connections Map, as seen April 2002), [Pathway]

J. Jia, K. Amanai, G. Wang, J. Tang, B. Wang, J. Jiang, Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature 416, 548-552 (2002). [Online Journal]