Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception

摘要

Sonic hedgehog protein fulfils many vital roles in establishing the body plan of multicellular organisms during development. And in adult organisms it regulates the stem cells that maintain organs and tissues. In the embryo, Sonic hedgehog is secreted by certain cells to create a concentration gradient; cells then measure this concentration to work out where they are, which allows them to develop into the right sort of cells. However, many details of this process are not completely understood. At the core of this process are the interactions between the Sonic hedgehog protein, a receptor called Patched1 that is found on plasma membranes, and another membrane protein called Smoothened. The job of Smoothened is to activate proteins that enter the cell nucleus and ‘switch on’ the pathway's target genes, which encode Patched1 and a number of other proteins. The role of Patched1, on the other hand, is to repress Smoothened. However, when sonic hedgehog binds to Patched1, the latter is unable to repress Smoothened. Increasing the production of Patched1 is thought to serve two main roles it prevents activation of the Sonic hedgehog pathway, and it prevents the Sonic hedgehog protein spreading to neighboring cells (by binding to it). But how is the level of Patched1 itself regulated? Yue et al. now report that two proteins, called Smurf1 and Smurf2, perform this regulation role in mammalian cells. Smurf1 and Smurf2 are enzymes that attach a molecule called ubiquitin to proteins, setting in train a series of events that leads to the degradation of the protein. Yue et al. now show that Smurf1 and Smurf2 recognize a signal on Patched1 and perform a similar modification, causing the Patched1 to be internalized through an alternate pathway and degraded in lysosomes. This series of events ultimately allow the Sonic hedgehog pathway to be activated. The work of Yue et al. exposes a critical enzymatic step that sorts unbound Patched1 receptors from those that are bound to Sonic hedgehog proteins. Further research is needed to determine if this signaling pathway can be manipulated for therapeutic purposes.