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The Hedgehog (Hh) pathway a signaling cascade that plays a crucial role in many fundamental processes, including embryonic development and tissue homeostasis in both vertebrates and invertebrates. Many studies have shown that deregulation of Hh pathway is associated with transformation and tumorigenesis as well as drug resistance in a multitude of cancers by driving cancer cell proliferation, malignancy, metastasis, and the expansion of cancer stem cells (CSCs)1.
Initially identified in Drosophila, core components of the Hh pathway are conserved in vertebrates. There are three paralogs of the invertebrate Hh gene in mammals; Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh). Shh is crucial for early development, inducing cell specialization in the central nervous system and patterning of the limbs, and IHH is involved with bone differentiation and skeletal development. Dhh is involved in the development of the gonads2,3.
When the pathway is inactive, the smoothened (Smo) protein is inhibited by the patched receptors (Ptch1 and Ptch2), preventing it from entering the plasma membrane. In this state, the pathway’s effectors, the Gli proteins (Gli2, a transcriptional activator, and Gli3, a repressor of transcriptional activity4,5) are associated with the negative regulator, suppressor of fused (Sufu)1. Phosphorylation of the Gli proteins by protein kinase A (PKA), glycogen synthase kinase-3 (GSK3), and casein kinase 1 (CK1), leads to their cleavage of the repressive Gli2R and Gli3R. The truncated forms then translocate to the nucleus and inhibit transcription of Hh-mediated genes1,5.
When present, a Hh protein such as Shh will bind to and inhibit Ptch1 and Ptch2 to activate the pathway. This is facilitated by the co-receptors Gas1, Cdon, and Boc, whilst Hh-interacting protein 1 (Hhip1) acts as a feedback antagonist of Hh signalling1,6. Inhibition of the patched receptors relieves the inhibition of Smo, allowing its phosphorylation and translocation into the plasma membrane of the primary cilium in association with another protein, Evc. Activation of Smo and its interaction with Evc leads to the movement of Gli proteins and Sufu through the primary cilium, aided by kinesin-family protein KIF7, and the dissociation of Gli proteins from Sufu2,7. This dissociation prevents the phosphorylation of the Gli proteins, allowing Gli activator (GliA) to be formed. GliA translocates to the nucleus, where it binds to the DNA and induces the expression of Gli target genes, which vary based on the tissue1,5.
This pathway poster provides an overview of the complex Hh signaling pathway in vertebrates. Discover the range of proteins involved in the Hh signaling pathway and find products including cell lines as well as antibodies relevant to your targets of interest.