Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy

Abstract

Summary The Hedgehog (Hh) signaling pathway governs complex developmental processes, including proliferation and patterning within diverse tissues. These activities rely on a tightly-regulated transduction system that converts graded Hh input signals into specific levels of pathway activity. Uncontrolled activation of Hh signaling drives tumor initiation and maintenance. However, recent entry of pathway-specific inhibitors into the clinic reveals mixed patient responses and thus prompts further exploration of pathway activation and inhibition. In this review, we share emerging insights on regulated and oncogenic Hh signaling, supplemented with updates on the development and use of Hh pathway-targeted therapies.

Dose-dependent transduction of Hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor Smoothened and the kinase Fused

“…Its deregulation leads to developmental disorders and cancers (Pak and Segal, 2016). In many cases, HH acts as a morphogen; it spreads as a gradient across a field of receiving cells to promote dose-dependent discrete transcriptional responses (Vervoort, 2000).…”

Nkx2-2as Suppression Contributes to the Pathogenesis of Sonic Hedgehog Medulloblastoma

“…Despite the established role of Gli transcription factors in canonical Shh signaling, the downstream molecular mechanisms that account for the development of Shh-type MBs remain to be elucidated (7). In this study, we found that the deregulation of a lncRNA, Nkx2-2as, contributed to carcinogenesis in the context of constitutively active Shh signaling in cerebellar granule cells.…”

“…Conversely, the Gli proteins are directly bound and antagonized by the suppressor of fused homolog (Sufu; refs. 7,8). As the best-studied Hedgehog homolog, Shh signaling accounts for nearly 30% of human MBs, with the most frequent mutations detected in Patched, Sufu, and SMO (9).…”

“…The Hedgehog pathway is a key regulator of ontogenesis, and aberrant Hedgehog signaling has been implicated in carcinogenesis (7). In the absence of the Hedgehog ligands, the inhibitory transmembrane receptor Patched prevents high expression and activity of the seven-membrane-spanning receptor Smoothened (SMO; refs.…”

“…In the absence of the Hedgehog ligands, the inhibitory transmembrane receptor Patched prevents high expression and activity of the seven-membrane-spanning receptor Smoothened (SMO; refs. 7,8). In mammalian cells, ligand engagement of Patched relieves SMO inhibition, allowing it to process and activate Gli transcription factors.…”