The Hedgehog (Hh) signal transduction pathway is an evolutionarily conserved signaling cascade essential for proper patterning and development of tissues in metazoan organisms.
A cellular signaling pathway that may determine epithelial cell fate in the esophagus is the Hedgehog (Hh) pathway. The Hh family of secreted proteins is required for proper development, differentiation, and growth of body regions in insects and vertebrates. In Drosophila, Hh determines correct antero-posterior patterning during embryonic segmentation and wing development55. Its three mammalian orthologs, Sonic (Shh), Indian (Ihh) and Desert (Dhh) hedgehogs, establish morphogenic gradients that specify correct axial patterning of the mammalian embryo. Hh proteins undergo autocleavage to an active N-terminal form (Hh-Np), which is then modified by the addition of a cholesterol moiety and palmitoylation before being secreted. Signaling in vertebrates begins with binding of Hh protein to the twelve-transmembrane receptor, Patched (Ptch). Ptch, in the absence of Hh ligand, inhibits the activity of the seventransmembrane protein Smoothened (Smo). Upon ligand binding, repression of Smo is released and signaling occurs through a cytoplasmic protein complex composed of Fused (Fu), Suppressor of fused (Su(fu)), and Gli transcription factors. Studies in Drosophila demonstrate that in response to Smo activity, Fu phosphorylates Su(fu) which dissociates from Cubitus interruptus (Gli orthologue in flies), promoting translocation of Cubitus interruptus into the nucleus. Once in the nucleus, Gli transcription factors transactivate pathway gene targets including Ptch and GUI. Thus, expression of Ptch and GUI proteins are indicators of pathway activation.
Another membrane-bound protein, Hedgehog-interacting protein (HIP), binds Hh ligands with equal affinity to Ptch. It is thought to regulate the availability of free Hh and attenuate Hh signaling. Inhibitors of the Hh pathway include cyclopamine, a naturally occuring veratrum alkaloid, and the monoclonal antibody 5E1. Cyclopamine acts downstream of Ptch by binding directly to Smo and changing its conformation. 5E1 was generated by the Jessell lab and binds to active Shh-Np and Ihh-Np, preventing either binding to Ptch. Current pharmaceutical efforts are focused on generating small molecule Smo antagonists.
The control of cell proliferation is one of the many roles subsumed by mammalian Hh signaling, particular among populations of central nervous system progenitor cells. Genetic activation of the pathway can cause also overgrowth of non-neuronal tissues. It first became apparent that derangement of this capacity could lead to human tumors when haploinsufficiency of Ptcl was found to be the causative lesion underpinning Gorlin syndrome, a constellation of precocious basal cell carcinoma, skeletal abnormalities and medulloblastoma. Nearly all cases of sporadic basal cell carcinoma are now known to be due to constitutive Hh signaling caused by genetic damage to pathway components. Derangements in the production of Hh ligand have also been implicated in the pathogenesis and growth of several other human tumor types. Importantly for the development of targeted therapies, at least some tumors initiated by genetic lesions to genes encoding Hh pathway components continue to be dependent upon pathway activity for subsequent growth. Mutational activation of the Hh pathway is associated with tumors of the skin, central nervous system, and skeletal muscle. Germline loss of function mutations in PTCH result in Gorlin's syndrome, characterized by cancer predisposition and craniofacial and limb defects associated with abnormal Hh signaling in development. Individuals with Gorlin's syndrome develop multiple basal cell carcinomas, medulloblastoma, and rhabdomyosarcoma.
Reference:David Hong-En Wang. HEDGEHOG SIGNALING IN ESOPHAGEAL DEVELOPMENT AND BARRETT'S ESOPHAGUS