Most cells in our bodies bear immotile hairlike protrusions called primary cilia (1). Only a few micrometers long, they are marvelously complex sensors, detecting and interpreting signals from the environment, such as light, odorants, fluid flow, and proteins that signal between cells. In each case, the receptor for the signal, along with some of the proteins that transmit the message into the cell, are localized in cilia. Their movement into and out of cilia controls signaling pathways that ultimately trigger responses such as cell division and differentiation. Thus, a central challenge is to understand how transmembrane proteins, especially receptors, are targeted to primary cilia. In humans, defective trafficking to cilia can cause pathological conditions ranging from cystic kidney disease to brain malformations and obesity (2). On page 1777 of this issue, Kovacs et al.(3) describe a new mechanism for the movement of the transmembrane protein Smoothened (Smo) into primary cilia. Smo is a component of the signaling pathway that responds to secreted proteins in the Hedgehog (Hh) family. The Hh pathway has been previously linked to cilia (4–6) and plays fundamental roles in development, stem cell function, and carcinogenesis (7). Sonic Hedgehog (Shh) is a secreted ligand that initiates signaling by binding to its receptor Patched 1 (Ptc1). In the absence of Shh, Ptc1 is concentrated in cilia and inhibits Smo activity (8). Shh binding to Ptc1 inactivates the receptor and causes Ptc1 to move out of cilia.

This allows the activation of Smo, which accumulates within the ciliary membrane (4). The movement of Smo to cilia brings it near other components of the signaling pathway, resulting in activation of transcription factors in the Gli family that regulate gene expression (9). Smo is a seven-pass transmembrane protein that resembles heterotrimeric GTP-binding protein (G protein)–coupled receptors.