Sonic Hedgehog Activates the GTPases Rac1 and RhoA in a Gli-Independent Manner Through Coupling of Smoothened to G _i ProteinsA Presentation from the 1st International HEALING Meeting: Hh-Gli Signaling in Development, Regeneration and Disease, Kolymbari, Crete, 23 to 25 June 2011.

Abstract

The vertebrate Hedgehog (Hh) pathway has essential functions during development and tissue homeostasis during normal physiology while its dysregulation is a common theme in cancer. The Hh ligands (Sonic, Indian, and Desert Hh), bind to the receptors Patched1 and 2, resulting in inhibition of their repressive effect on Smoothened (Smo). Smo is a 7-transmembrane protein, which was only recently proved to function as a GPCR with specificity toward Gi. In addition to Gi activation, Smo signals via its C-tail to inhibit Suppressor of Fused (Sufu), resulting in stabilization and activation of the Gli family of transcription factors, which execute a transcriptional response to the so-called “canonical Hh signaling”. In this presentation we illustrate two outcomes of Hh signaling that are independent of Gli transcriptional activity and, thus, are defined as “non-canonical”. One outcome is dependent on Smo coupling to Gi proteins and exerts changes in the actin cytoskeleton via stimulation of RhoA and Rac1. These cytoskeletal changes promote migration in fibroblasts and tubulogenesis in endothelial cells. The other non-canonical Hh pathway is independent of Smo, and consists of inhibition of Patched1-induced cell death.

The transition from differentiation to growth during dermomyotome-derived myogenesis depends on temporally restricted hedgehog signaling

“…Alternatively, Shh might signal the DM by removing a Gli3-mediated repressor activity, as cell death observed in the DM of Shh −/− embryos was prevented in Shh-Gli3 compound mutants. The possibility also remains open that the mouse DM responds to Shh via a Gli-independent non-canonical pathway (Polizio et al, 2011).…”

Sonic hedgehog signaling in kidney fibrosis: a master communicator

“…Another non-canonical Shh signaling mainly controls endothelial cells cytoskeletal reorganization and fibroblast migration through activating small GTPases and regulating fluctuations of calcium ions upon stimulation of Shh (Chinchilla et al, 2010; El-Zaatari et al, 2010; Polizio et al, 2011). It has been demonstrated that none of the three hedgehog ligands are able to induce Gli-target genes in human umbilical vein (HUVeC) or human cardiac microvascular endothelial cells (HMVeC), indicating that endothelial cells do not respond to hedgehog through the canonical pathway.…”

“…It has been demonstrated that none of the three hedgehog ligands are able to induce Gli-target genes in human umbilical vein (HUVeC) or human cardiac microvascular endothelial cells (HMVeC), indicating that endothelial cells do not respond to hedgehog through the canonical pathway. However, all three hedgehog proteins promote endothelial cell tubulogenesis in 3D cultures in a Smo-dependent manner (Polizio et al, 2011). Consistent with the required cytoskeletal rearrangement for tubulogenesis, Shh, Ihh and Dhh all stimulate the small GTPase RhoA and actin stress fibers formation (Chinchilla et al, 2010).…”

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

“…In addition, cells from colon carcinoma expressing shRNA against Ptch1 or Gli1 lose epithelial morphology, and increase their capacity for migration and expression of EMT-related genes, such as FOXC2, vimentin, Snail1 and ZFHX1B, while the expression of E-cadherin is decreased [117]. Shh can stimulate the small GTPases Rac1 and RhoA, resulting in the migration of the cells in a SMO-dependant but Gli-independent mechanism, which is therefore related to a ''non-canonical'' Hh pathway [118,119].…”