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Evidence for a novel feedback loop in the Hedgehog pathway involving the seven transmembranedomain protein Smoothened and the kinase Fused.
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International audience. Hedgehog (HH) is a major secreted morphogen involved in development, stem cell maintenance and oncogenesis[1, 2].In Drosophila wing imaginal discs, HH produced in the posterior compartment diffuses into the anterior compartment to control target gene transcription via the transcription factor Cubitus interruptus (CI). The first steps in reception and transduction of the HH signal are mediated by its receptor Patched (PTC)[3] and the seven-transmembranedomain protein Smoothened (SMO) [4, 5]. PTC and HH control SMOby regulating its stability, trafficking and phosphorylation (for review see [6]). SMO interacts directly with the Ser-Thr protein kinase Fused (FU) and the kinesin-related protein Costal2 (COS2), which interact with each other and with CI in an intracellular “Hedgehog transducing complex”[7-9].We show here that HH induces FUtargeting to the plasma membrane in a SMO-dependent fashion and that,reciprocally,FUcontrols SMO stability and phosphorylation. FUanchorage to the membrane is sufficient to make it a potent SMO-dependent, PTC-resistant, activator of the pathway. These findings reveal a novel positive-feedback loop in HH transduction and are consistent with a model in which FU and SMO, by mutually enhancing each other's activities, sustain high levels of signalingand render the pathway robust to PTClevel fluctuations.
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