1. Date of download: 6/21/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved. The hedgehog (Hh) signaling—a proliferative pathway especially important in embryogenesis, stem cell and progenitor cell development, and carcinogenesis. Hh ligands are secreted proteins covalently modified by palmitate and cholesterol. They act in autocrine, paracrine, or endocrine manner through their membrane receptor Patched (Ptch), which is the key inhibitor of Hh signaling in the unligated form (Katoh and Katoh, 2008). In the absence of Hh (as in the left side of the figure) Ptch impedes the Hh pathway by inhibiting the activity of Smoothened (Smo), a positive regulator of signaling. According to the model presented in the figure, Ptch is a sterol pump that exports sterols (cholesterol or an oxysterol), thereby removing these activator molecules from Smo and making Smo idle. The repression of Smo by Ptch incapacitates the downstream Hh effectors, the glioma-associated family of transcription factors (Gli). This occurs partly because Gli is suppressed by Sufu (suppressor of fused) and partly because protein kinases, such as the dual-specificity tyrosine- (Y)-phosphorylation regulated kinase (DYRK), casein kinase 1 (CK1), and glycogen synthase kinase 3 (GSK), phosphorylate Gli, thereby marking Gli for ubiquitination by a ubiquitin ligase (E3) and subsequent degradation by the proteasome. Binding of Hh to Ptch (as in the right side of the figure) abrogates its sterol-exporting activity; therefore, the sterol can activate Smo. In a manner incompletely understood, the active Smo suppresses Sufu, thereby permitting Gli activation, and activates mitogen- activated protein kinase kinase kinase 10 (MAP3K10), which in turn phosphorylates and inhibits DYRK, thereby preventing phosphorylation, ubiquitination, and proteasomal degradation of Gli. Thereafter the active Gli accumulates in the cell, translocates into the nucleus, and binds to its target genes. Hh signaling thus upregulates the transcription of numerous genes, including those that encode Ptch and Gli (a positive feedback loop), cyclin-D1 and -D2 (for cell cycle acceleration), several transcription factors such as those of the Forkhead box protein family (for cell fate determination), receptor ligands such as Jagged 2 (a ligand protein that activates Notch and related receptors), and ligand-binding proteins such as the Secreted frizzled-related protein 1 (SFRP1) that binds Wnt protein, thus preventing Wnt signaling (Fig. 3-13). Chemicals that activate or inhibit Smo (shown in the left and right sides of the figure, respectively) may interfere with embryonic development. For example, the plant alkaloid cyclopamine inhibits Smo and causes cyclopia, a birth defect, in lambs. Smo inhibitors are potentially anticarcinogenic, whereas Smo activators may promote carcinogenesis by increased Hh signaling. Inactivating mutation of Ptch, the main inhibitor of Hh signaling, typically occurs in basal cell carcinoma of the skin that may be induced by UV and ionizing radiation, as well as arsenic exposure (Tang et al., 2007). SAG, Smoothened Agonist; SANT-1, Smoothened Antagonist 1. Legend : From: Mechanisms of Toxicity Casarett and Doull's Toxicology: The Basic Science of Poisons, 8e, 2012 From: Mechanisms of Toxicity Casarett and Doull's Toxicology: The Basic Science of Poisons, 8e, 2012