Page 81 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy
P. 81

 Abstract
Hedgehogs constitute a family of pivotal morphogens that exert their action through a well-characterized canonical pathway involving Gli transcription factors and as yet poorly characterized non-canonical signaling. To obtain more insight in the non- canonical aspect of Hedgehog signaling, we perform a comprehensive characterization of the cellular kinome in Hedgehog-challenged wild-type, Ptc-/-, Smo-/-, and Smo-agonist Purmophamine-challenged wild-type fibroblasts. We observe that whereas non-canonical Hedgehog signaling in general displays an absolute requirement for the presence of functional Ptc, an elaborate signaling network of both Smo-dependent and independent pathways is present that mediates actin reorganization through the activation of Src-like kinases, activates various proinflammatory signaling cascades and concomitantly canonical Wnt and Notch signaling while suppressing canonical BMP signaling. The observation that Ptc- dependent Smo-independent non-canonical Hedgehog signaling increases Wnt/Notch provides an obvious explanation for the failure of Smo antagonists in combating gastrointestinal cancer and suggests that therapy should be directed at inhibiting Hedgehog-Ptc interaction.
Keywords: Sonic; Hedgehog; Transcription; Cytoskeleton; Endocytosis.
                                 Noncanonical Hedgehog signaling
Noncanonical Hedgehog signalling
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