Fig. 9. The model: three states of Smoothened translate Hh levels into distinct responses. Smo can adopt three states, a decision normally dictated by Hh, via Ptc. The Ci regulatory complex, which includes full-length Ci, Cos and Fu, likewise can adopt three states (Ingham and McMahon, 2001). In the absence of Hh (A) Smo is OFF. Its cytoplasmic aspect is unavailable for signaling. The Cos/Fu/Ci regulatory complex is anchored to microtubules and promotes efficient processing of Ci155 to CiR. Low levels of Hh (B) expose Cos inhibitory sites in the cytoplasmic tail of Smo. Cos interaction with these sites drives the Ci regulatory complex into the low state, which recruits Sufu and makes little CiR or CiA. high levels of Hh (C) drive a major change in Smo, possibly dimerization. This allows the cytoplasmic tails of Smo to cooperatively activate Fu and Cos. Fu* and Cos* then cooperate to inactivate Sufu, to block CiR production, and to produce CiA at the expense of Ci155.