Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease

Abstract

The Hh/GLI signaling pathway was originally discovered in Drosophila as a major regulator of segment patterning in development. This pathway consists of a series of ligands (Shh, Ihh, and Dhh), transmembrane receptors (Ptch1 and Ptch2), transcription factors (GLI1–3), and signaling regulators (SMO, HHIP, SUFU, PKA, CK1, GSK3b, etc.) that work in concert to repress (Ptch1, Ptch2, SUFU, PKA, CK1, GSK3b) or activate (Shh, Ihh, Dhh, SMO, GLI1–3) the signaling cascade. Not long after the initial discovery, dysregulation of the Hh/GLI signaling pathway was implicated in human disease. Activation of this signaling pathway is observed in many types of cancer, including basal cell carcinoma, medulloblastoma, colorectal, prostate, pancreatic, and many more. Most often, the activation of the Hh/GLI pathway in cancer occurs through a ligand-independent mechanism. However, in benign disease, this activation is mostly ligand-dependent. The upstream signaling component of the receptor complex, SMO, is bypassed, and the GLI family of transcription factors can be activated regardless of ligand binding. Additional mechanisms of pathway activation exist whereby the entirety of the downstream signaling pathway is bypassed, and PTCH1 promotes cell cycle progression and prevents caspase-mediated apoptosis. Throughout this review, we summarize each component of the signaling cascade, non-canonical modes of pathway activation, and the implications in human disease, including cancer.

Basaloid Follicular Hamartoma of the Eyelid: A Case Report and Literature Review about an Unusual Lesion in the Ocular Region

“…Interestingly, in the ocular region APC gene mutations have been associated with pigmented ocular fundus lesions [ 18 , 19 ]. Remarkably, previous genetic studies found an association between BFH and PTCH1 gene mutations, which is a gene that normally encodes the patched-1 protein that acts as the receptor for the Sonic Hedgehog (SHH) protein [ 1 , 20 , 21 ]. The SHH pathway is fundamental in numerous aspects of embryonic development [ 20 , 22 , 23 ].…”

“…The SHH pathway is fundamental in numerous aspects of embryonic development [ 20 , 22 , 23 ]. Dysregulation of the SHH signalling might lead to increased cellular proliferation and triggering tumour formation [ 21 , 23 , 24 ].…”

Cancer-Associated Fibroblasts and Tumor Cells in Pancreatic Cancer Microenvironment and Metastasis: Paracrine Regulators, Reciprocation and Exosomes

“…This ligand-receptor complex loses repressive effect of Smoothened (SMO). Active SMO inhibits suppressor of fused homolog (SUFU), leading to release and activation of glioma-associated oncogene homolog (GLI) transcription factors, where GLI1 itself is a part of transcriptional targets (Figure 2) [34]. SHH from tumor cells in turn induces expression of growth factors insulin growth factor 1 (IGF1) and growth arrest-specific 6 (GAS6) in PSCs.…”

Research progress on the hedgehog signalling pathway in regulating bone formation and homeostasis

“… 3 In addition, certain co‐receptors, like growth arrest specific (Gas), has been demonstrated to interact with Hh ligands to activate the Hh signalling, whereas for hedgehog interacting protein (HHIP), a membrane glycoprotein which could bind all the Hh ligands was found to negatively modulate the Hh signalling by preventing the interaction between Hh ligands and Ptch and finally attenuated the Hh signals. 4 …”