Hedgehog, Patched and Dispatched near the basement.

C ell signaling is arguably the most important characteristic of multicellular organisms. Without cell signaling, the different cells in the body of a plant or animal could not communicate with each other, and they could not coordinate their actions. Such coordination is essential: first, to build a complex body composed of thousands or millions of cells and second, for the correct performance of such a body in everyday life, whether acquiring nutrients, excreting toxins, or dealing with hostile or friendly interactions from other organisms. This coordination is corroborated by the many problems and diseases (such as developmental abnormalities and cancers) that arise from malfunction of the cellular machinery that deals with cell signaling and communication (1–3). Thus, the study of such cell signaling machinery is receiving a great deal of attention bybiological and medical research. At the most basic level, any cell signaling process must involve a signal, synthesized or otherwise, generated by the sending cell and some kind of system to receive that signal and respond to it in the receiving cell. An article by Callejo et al. (4) in PNAS sheds light on the first aspect of the process by providing crucial information on the mechanism for the release and transport of the signaling protein Hedgehog (Hh). Their findings show that a crucial step in Hh signaling is trafficking and recycling within the sending cell itself. Their findings, however, resonate with and are relevant to research on other signaling proteins. Cells in many tissues organize themselves in epithelia (that is, single cell-thick sheets of cells with distinctive apical, lateral and basal surfaces). Cells within epithelia are, thus, polarized, and this fact has clear functional consequences. For example, in the gut, the apical surface faces the lumen and secretes digestive enzymes and other products, whereas the basal surface attaches the cells to a basement membrane composed of extracellular matrix. Because of these precedents, it might be easier to think that the natural place for signaling molecules to be secreted is the apical surface. However, it is being increasingly recognized that this polarization is exploited in a much more complex way during cell signaling (5) and that the secretion and traffic of signaling molecules may happen apically, basally, or apparently, at both cell surfaces. For example, the secretion of the signaling protein Wingless (Wg; a member of the Wnt family) was deemed to occur mostly apically (6) and subsequently, basally (7) all in the same tissue used in the work by Callejo et al. (4), the developing fly wing and likewise the signaling protein Decapentaplegic (Dpp; a member of the TGF-β family) (8). Because the properties of the extracellular medium change from the apical to the basal sides, the secretion of a signaling molecule at either side will affect its mode of transport, range, speed of diffusion, and even the type of receptors that it may have access to in the receiving cell; hence, knowledge of the place of secretion is a fundamental piece of the signaling jigsaw. Secretion of Hh has been reported to occur apically (9), but the available data suggested a complex process. The Hh protein is first produced as a long precursor, which then needs to be cleaved, and the active or mature fragment needs to be modified by the addition of lipids (3). The molecular purpose of these modifications has been hotly debated, because engineered versions of Hh that cannot have lipids added to them are able to travel even farther that WT Hh (11). In addition, the range of the Hh protein is limited by its receptor Patched (Ptc), because after binding, internalization, and signaling, the Hh protein is degraded in the receiving cell. In turn, the expression of Ptc is up-regulated by Hh signaling in a feedback control mechanism also shared by Wg and Dpp signaling (8, 10). Finally, the proteins Dally-like (Dlp), Dispatched (Disp), and Interference Hh (Ihog) have also been linked to Hh trafficking, APICAL