Hedgehog signaling update

Abstract

In vertebrate hedgehog signaling, hedgehog ligands are processed to become bilipidated and then multimerize, which allows them to leave the signaling cell via Dispatched 1 and become transported via glypicans and megalin to the responding cells. Hedgehog then interacts with a complex of Patched 1 and Cdo/Boc, which activates endocytic Smoothened to the cilium. Patched 1 regulates the activity of Smoothened (1) via Vitamin D3, which inhibits Smoothened in the absence of hedgehog ligand or (2) via oxysterols, which activate Smoothened in the presence of hedgehog ligand. Hedgehog ligands also interact with Hip1, Patched 2, and Gas1, which regulate the range as well as the level of hedgehog signaling. In vertebrates, Smoothened is shortened at its C-terminal end and lacks most of the phosphorylation sites of importance in Drosophila. Cos2, also of importance in Drosophila, plays no role in mammalian transduction, nor do its homologs Kif7 and Kif27. The cilium may provide a function analogous to that of Cos2 by linking Smoothened to the modulation of Gli transcription factors. Disorders associated with the hedgehog signaling network follow, including nevoid basal cell carcinoma syndrome, holoprosencephaly, Smith-Lemli-Opitz syndrome, Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, Carpenter syndrome, and Rubinstein-Taybi syndrome.

Dichotomy in Hedgehog Signaling between Human Healthy Vessel and Atherosclerotic Plaques

“…( Figure 1) (10). The in vivo relevance of the induction of these genes was proven in ischemia experiments, in which intramyocardial gene transfer of SHH promoted recovery and preservation of left ventricular function in myocardial ischemia by enhanced neovascularization (11), supporting the notion that HH aids in ischemic tissue rescue and especially in its revascularization.…”

“…Under HH-unligated conditions, PTCH1 keeps a second transmembrane receptor called Smoothened (SMO) inactive (9). In mammals, this probably involves translocation of a vitamin D3-like 3-β hydroxysteroid (10 ates signaling through the gliomaassociated (GLI) transcription factors, resulting in the transcription of target genes, including both GLI1 and PTCH1…”

Hedgehog/hyaluronic acid interaction network in nonalcoholic fatty liver disease, fibrosis, and hepatocellular carcinoma

“…2 Interestingly, Guy and colleagues 1 observed a significant correlation between nuclear accumulation of GLI2, liver fibrosis, and other risk factors for NAFLD. Accordingly, we found that GLI2 was overexpressed in liver extracts from rats treated with high fat/high fructose (HF/HFr) diet as compared with standard diet (Fig.…”

New Targets for Therapy in Pancreatic Cancer

“…After Hh binding, PTCH1 is internalized and degraded, allowing Smo to translocate to the cell membrane where it initiates a downstream signalling responsible for the release of the glioma-associated (Gli) proteins from the inhibitor complex Suppressor of Fused (SUFU). The subsequent activation and nuclear translocation of Gli transcriptional factors results in increased expression of genes encoding for growth factors, cell cycle regulators, cell adhesion molecules, matrix proteins, other transcription factors, and inhibitors of the Hh pathway itself (Cohen, 2010;Ruiz i Altaba et al, 2002).…”