Mechanisms and functions of Hedgehog signalling across the metazoa

Ingham, Philip W.; Nakano, Yoshiro; Seger, Claudia

doi:10.1038/nrg2984

Cited by 542 publications

(517 citation statements)

References 155 publications

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“…18 There are three secreted Hh ligand family member proteins: Sonic Hh (Shh), Indian Hh and desert Hh. 25,26 Hh signaling depends on the balance between activator and repressor forms of the glioma-associated oncogene family (Gli) of zincfinger transcription factors. The basic signaling pathway involves a 12-transmembrane domain receptor protein Patched 1 (Ptc1), the 7-transmembrane domain protein Smoothened (Smo), the suppressor of fused protein (Sufu) and the Gli transcription factors.…”

Section: Cilium: Structure and Signalingmentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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Motile and primary cilia (PC) are microtubule-based structures located at the cell surface of many cell types. Cilia govern cellular functions ranging from motility to integration of mechanical and chemical signaling from the environment. Recent studies highlight the interplay between cilia and autophagy, a conserved cellular process responsible for intracellular degradation. Signaling from the PC recruits the autophagic machinery to trigger autophagosome formation. Conversely, autophagy regulates ciliogenesis by controlling the levels of ciliary proteins. The cross talk between autophagy and ciliated structures is a novel aspect of cell biology with major implications in development, physiology and human pathologies related to defects in cilium function. Cell Death and Differentiation (2015) 22, 389-397; doi:10.1038/cdd.2014.171; published online 31 October 2014 FactsAutophagy is a degradative and recycling mechanism that allows cells to adapt to stress situations including nutrient deprivation. Primary cilia (PC) and motile cilia (MC) are sensory structures at the cell surface. PC sense nutrient, growth factor and calcium changes in the extracellular environment and also respond to mechanical stress. MC are beating structures that contribute to innate defense in the lung, for example. The PC is a site for the recruitment of autophagy-related (ATG) proteins that mediate autophagosome formation in response to cilium-dependent signaling. In turn, autophagy regulates the biogenesis of cilia by degrading certain proteins involved in cilia formation. Modulation of autophagy represents a new therapeutic opportunity in diseases related to defective cilia function. Open QuestionsHow are ATG proteins transported to the PC? How do ATG proteins recruited to the PC contribute to the biogenesis of phagophores and autophagosomes? Ciliary proteins are degraded by autophagy. How selective is this degradative pathway? Do some of these proteins contain motifs that result in selective engulfment by autophagosomes?What are the determinants that switch the degradation of ciliary proteins between basal and induced autophagy? Is there any specific function for cilium-dependent autophagy in ciliated cells? Do signals that trigger cilium-dependent autophagy depend on the stimuli (chemical, mechanical) or do all stimuli converge to a single signaling pathway upstream of the autophagy machinery? Can modulation of autophagy contribute to the restoration of cilium functions?Receptors, transporters and specialized plasma membrane structures such as cilia constitute the interfaces between the extracellular and intracellular milieu and allow the cells to trigger specific responses to adapt to changes imposed by the environment. Among these adaptive responses, macroautophagy (hereafter referred to as 'autophagy') is a catabolic process conserved in eukaryotic cells by which the cell recycles its own constituents. 1 Autophagy is involved in the adaptation to starvation, cell differentiation and development, the degradation of aberrant structure...

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Section: Cilium: Structure and Signalingmentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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“…Signals of the Hh (Hedgehog) pathway are essential in directing cell proliferation and patterning during embryogenesis (Hooper & Scott, 2005; Ingham et al , 2011). The pathway lays at the cross‐road of cell survival and differentiation decisions, and unscheduled Hh signaling can lead to hyperproliferation and the development of malignancies.…”

Section: Introductionmentioning

confidence: 99%

“…Hh signaling is initiated at the cell membrane by the inactivation of the 12‐pass transmembrane receptor Ptch (Patched) upon binding of the Hh ligands (Ingham et al , 2011). Ptch inactivation frees the cognate receptor Smo (Smoothened) leading to the downstream activation of a transcriptional program mediated by Gli1, Gli2, and Gli3 (Glioma‐associated oncogene homolog 1, 2, and 3) transcription factors (Hui & Angers, 2011).…”

Section: Introductionmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.

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“…We therefore explored whether the Hh pathway is involved in the regulation of Yki signaling in ECs and thus maintains the proper development of early germline. The Hh pathway plays evolutionarily conserved roles in controlling a wide variety of developmental processes, such as pattern formation, growth control and stem cell regulation [39,40]. In Drosophila ovary, loss of hh results in follicle stem cell loss and defects in germ cell differentiation [28,38,41].…”

Section: Hh Signaling Supports Niche Function By Modulating Hippo Sigmentioning

confidence: 99%