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The Hedgehog proteins, highly conserved in vertebrates and invertebrates, are a family of secreted intercellular signaling molecules originally identified by genetic analysis of embryonic mutants of the Drosophila melanogaster (1,2). Hedgehog ligands are critical in governing embryonic development and adult tissue homeostasis. They play an crucial role in the regulation in nearly all cellular processes including angiogenesis and neovascularization (1–3). Hedgehog proteins signal via two, multi-transmembrane proteins, named PATCHED and SMOOTHENED (4,5). In this receptor complex, PATCHED is the ligand-binding subunit, while SMOOTHENED is the signaling component. Upon binding of HH to its receptor PATCHED1, an inhibitory effect of PATCHED on SMOOTHENED is released, allowing SMOOTHENED to trigger a signaling cascade that activates the GLI transcription factors (GLI 1, 2 and 3), which are essential effectors for Hedgehog-mediated cellular effects (5). In the absence of ligand, the Hedgehog signaling pathway is inactive. In this case, the transcription factors GLI undergo phosphorylation-dependent degradation. As a consequence, transcriptional activation of Hedgehog target genes is repressed. Pathway activation results in de-repression of SMOOTHENED, the central transducer for the signal, initiating a cascade that leads to the activation of GLI in the nucleus and regulation Hedgehog target genes (5,6).
In this study by Pilar Chinchilla and colleagues, the authors have identified a novel Hedgehog pathway independent of GLI transcription factors (7). This pathway activated by all three Hedgehog ligand (SONIC, INDIAN and DESERT) promotes vessel formation in endothelial cells. Angiogenesis is a coordinated multistep process involving endothelial cell proliferation, migration, and formation tubular structures. The authors have found that endothelial cells do not respond to Hedgehog through the canonical pathway. None of the Hedgehog ligands were able to promote GLI transcriptional activity in endothelial cells. However, all three ligands increased endothelial cell tubulogenesis in a SMOOTHENED-dependent manner. Hedgehog induces the typical elongated morphology of activated endothelial cells. Analysis of the mechanism showed that Hedgehog requires an intact Gi protein function to form tubes. This Hedgehog stimulated SMOOTHENED-Gi axis activates through RAC1 the small GTPase RHOA and the formation of actin stress fibers in endothelial cells, a step that is key for tube organization. In addition to regulating the actin cytoskeleton, the Hedgehog ligands contribute to the angiogenic process by increasing endothelial cell survival through the inhibition of the pro-apoptotic effect of unligated PATCHED receptor. Interestingly, this effect is a SMOOTHENED-independent manner and involves the reduced CASPASE activation in response to pro-apoptotic stimuli (e.g. serum starvation). Thus, this study defines a novel non-canonical Hedgehog pathway and shifts the paradigm of Hedgehog signaling by supporting the existence of GLI-independent regulated cellular functions. Together these findings not only provide a novel insight into the biology of the Hedgehog cascade but could also serve as foundation for the development novel therapeutics and diagnostic approaches for diseases dependent on an active Hedgehog pathway.
MEFZ was supported by the Schulze Center for Novel Therapeutics, Mayo Clinic Cancer Center, Division of Oncology Research, Miles and Shirley Fiterman Center for Digestive Disease, NCI CA136526, Mayo Clinic Pancreatic SPORE P50 CA102701, and Leukemia and Lymphoma Society Translational Research Program.