Hedgehog (Hh) is a secreted signaling protein that regulates tissue patterning during development by binding to Patched (Ptc), its cell surface receptor. Signal transmission is accommodated by another cell surface protein called Smoothened (Smo), and it is thought that a preformed complex of Ptc and Smo inhibits Smo-mediated signaling. When Hh binds Ptc, a conformational change is thought to relieve Ptc-mediated repression of Smo. Denef et al. propose a different mechanism by which Ptc regulates Smo activity. Analysis of Ptc and Smo in Drosophila cells indicates that Hh binding causes a decrease in the amount of Ptc at the cell surface, but increased Smo localization to the cell surface. Smo phosphorylation also increased. By using inhibitors, the authors propose that in the absence of Hh, Ptc promotes dephosphorylation of Smo through a type 2A protein phosphatase. Upon Hh binding to Ptc, this phosphatase may become inactive, resulting in increased Smo phosphorylation and activation, as well as localization to the cell surface where it can transduce signals. Hence, Ptc activation of Smo may be more indirect than was previously thought.
Denef, N., Neubuser, D., Perez, L., and Cohen, S.M. (2000) Hedgehog induces opposite changes in turnover and subcellular localization of Patched and Smoothened. Cell 102: 521-531. [Online Journal]