Patching the gaps in Hedgehog signalling
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1 Patching the gaps in Hedgehog signalling Rajat Rohatgi and Matthew P. Scott The Hedgehog (Hh) pathway plays central roles in animal development and stem-cell function. Defects in Hh signalling lead to birth defects and cancer in humans. The first and often genetically damaged step in this pathway is the interaction between two membrane proteins Patched (Ptc), encoded by a tumour suppressor gene, and Smoothened (Smo), encoded by a protooncogene. Recent work linking Hh signalling to sterol metabolites and protein-trafficking events at the primary cilium promises to shed light on the biochemical basis of how Patched inhibits Smoothened, and to provide new avenues for cancer treatment. The Hh pathway, elucidated initially through genetic analyses of Drosophila embryo segmentation, controls the development of most tissues and organs during development 1,2. In perhaps its best-known role, the Hh ligand functions as a morphogen in tissues such as the neural tube, with different concentrations of the ligand directing the adoption of different cell fates. In other contexts, Hh signalling drives the proliferation of precursor cells in tissues such as the skin and cerebellum, or mediates interactions between epithelial and mesenchymal compartments that sculpt organs such as the lung. Consistent with these many roles of Hh in development, severe birth defects are observed in mice and humans with quantitative defects in Hh signalling 3. Embryonic functions of Hh signalling are recapitulated in the adult animal, where the pathway regulates tissue stem cells required for organ repair and maintenance 4,5. The importance of adult Hh functions is reflected in loss of growth control when the pathway is damaged. Mutations that lead to constitutive Hh signalling cause Gorlin s syndrome, a familial cancer syndrome characterized by neoplasms that include basal cell carcinomas (BCC) and medulloblastomas 6,7. Inappropriate activation of the pathway has been implicated in the pathogenesis of sporadic human cancers Rajat Rohatgi and Matthew P. Scott are in the Departments of Developmental Biology, Genetics, and Bioengineering and Department of Oncology, Howard Hughes Medical Institute, Clark Center West W252, 318 Campus Drive, Stanford University School of Medicine, Stanford, CA , USA. mscott@stanford.edu Negative regulators Transcription factor Protein Kinase A (PKA) repressor Ligand 12-pass transmembrane receptor 7-pass transmembrane transducer of the skin, brain, lung, prostate, pancreas and gastrointestinal tract 5,8. These properties place Hh signalling at the critical nexus between organ stem cells and carcinogenesis. A detailed understanding of Hh signalling, together with the discovery and refinement of drugs capable of modulating the pathway, will have important implications for both cancer treatment and regenerative medicine. The Hedgehog pathway The overall structure of the Hh pathway consists of a series of repressive interactions (Fig. 1) 1,2,9. In the absence of ligand, target-gene transcription is repressed by a 12-pass transmembrane receptor protein, Ptc. Ptc inhibits the function of a 7-pass transmembrane protein, Smo. Ptc is inhibited by its ligand, the secreted Hedgehog protein (Hh in flies, and one of three proteins Sonic hedgehog (Shh) Patched (Ptc) Smoothened (Smo) Suppressor of Fused (SuFu) activator Figure 1 Basic structure of the mammalian Hedgehog signalling pathway. Positive regulators are shown in green boxes and negative regulators in red boxes. Abbreviations for the proteins used throughout the text are given in parentheses. Only the core, most extensively studied proteins in the pathway are shown. For more exhaustive diagrams consult recent reviews 2,9. in mammals: Sonic Hedgehog (Shh), Indian Hh (Ihh) and Desert Hh (Dhh)). Inhibition of Ptc by Hh ligands unleashes Smo activity through an unknown mechanism. In mammals, Smo somehow inhibits Suppressor of Fused (SuFu), a negative regulator of the pathway, leading to activation or derepression of target-gene transcription through three (1 3) transcription factors. 1 and 2 mainly function as transcriptional activators, wherase 3 exists in two forms a full-length transcriptional activator (3A) or an amino-terminal fragment that functions as a repressor (3R; Fig. 1). Here, we discuss recent work that sheds light on the first step in Hh signalling the longstanding mystery of how Ptc inhibits Smo. Several other steps in mammalian Hh signalling are also poorly understood, including how the signal is transduced from Smo through SuFu nature cell biology volume 9 number 9 SEPTEMBER
2 Pp Ee Rr Ss Pp Ee Cc Tt Ii Vv Ee Control +Shh Tubulin to the proteins. We have chosen to focus on the Ptc Smo interaction because it is the most frequently disrupted step in Hh pathway-related cancers. Patients with Gorlin s syndrome are heterozygous for the gene encoding Ptc1 (PTCH1) and their tumours often display loss-of-heterozygosity for the remaining functional allele of PTCH1 (refs 6, 7). Human SMO is a protooncogene, consistent with its role as a positive regulator in the pathway. Mutations that lead to a constitutively activated Smo protein have been observed in 10 20% of sporadic BCCs and 5% of sporadic medulloblastomas; PTCH mutations have also been identified in a substantial fraction of sporadic BCCs and medulloblastomas 3. A two-state model for Smo function A single smo gene is required in insects and mammals for transduction of the Hh signal in cells exposed to the Hh ligand 1. Smo is related to the Frizzled (Fzd) family of 7-pass transmembrane receptors, which possess a ~250 amino acid N-terminal cysteine-rich domain (CRD) 10. Smo and Fzd are often included in a sub-family of G-protein coupled receptors (GPCRs) that contain large N-terminal domains; these GPCRs often bind glycoproteins 10. Although Fzd directly interacts with Wnt ligands through the CRD, there is no evidence that Smo interacts with a protein ligand. Smo is generally thought to be regulated by an undiscovered small molecule, rather than a protein ligand. The main reason for this conclusion is the discovery of various small molecules that, when administered to cells, bind Smo and either activate or inhibit its function. The plant alkaloid cyclopamine was first Smo Tubulin Smo DAPI Figure 2 Hedgehog signal transduction at the primary cilium. Endogenous Smo in NIH3T3 fibroblasts treated with Shh localizes to the primary cilium. A three-colour confocal image shows Smo (green) detected with an anti-smo antibody, primary cilia (red) detected with an antibody against the ciliary marker anti-acetylated tubulin and nuclei (blue) detected with DAPI staining. White arrows indicate cilia. NIH3T3 cells were treated with Shh-conditioned medium or control medium for 24 h then fixed, permeabilized and processed for immunofluorescence microscopy with the indicated antibodies 48. (R. Rohatgi and M. Scott, unpublished data). identified as an inhibitor of Hh signalling because it was teratogenic in sheep, and later was shown to directly bind and inhibit Smo 11. A variety of small-molecule screens for Hh-pathway modulators have identified activators and inhibitors of the pathway that act on Smo One such Smo antagonist has entered Phase I clinical trials for the treatment of BCCs 8. These molecules seem to bind to a single site within the heptahelical domain of Smo, based on their ability to compete with fluorescently labelled cyclopamine 11. The susceptibility of Smo to numerous small molecules suggests that an endogenous ligand regulates its activity, as is the case for many GPCRs. By analogy to kinetic models of GPCR function, it has been proposed that Smo exists in two conformations, an active state and an inactive one 14,15. Without ligand, the baseline signalling activity of the receptor depends on the equilibrium between both states and the total number of receptors in the cell. Overproduction of Smo in cultured cells leads to a Hh-independent increase in the basal level of Hh target-gene transcription, consistent with this two-state equilibrium model 14. In this scenario, Ptc would function either by stabilizing Smo in its inactive state or by destabilizing its active state; Smo inhibitors, such as cyclopamine, function by stabilizing its inactive state. Certain smo point mutants (such as SMO M2, which is observed in BCCs) encode constitutively activated Smo proteins. Such subtly altered proteins are likely to modify the equilibrium in favour of the active state and allow Hh signalling even in the absence of Shh 14. Analogous ligand-independent activating mutations have also been isolated for several GPCRs 16. High-affinity inhibitors Focus on DEVELOPMENT AND DISEASE can block Smo M2 activity and thus are useful for the treatment of tumours driven by Shhindependent signalling 14. Although an endogenous small molecule that modulates Smo has not been identified, sterol-like molecules have emerged as leading candidates. In vertebrates, sterol levels can dramatically influence the responsiveness of a cell to Shh 17,18. Pharmacological depletion of sterols from fibroblasts reduced their ability to activate Hh target genes 19. Human patients, and mice with defects in enzymes responsible for cholesterol biosynthesis, have phenotypes consistent with a lack of Hh signalling 20. Two groups have recently shown that specific oxysterols (synthesized from cholesterol by hydroxylation of the iso-octyl side chain) can activate Hh signalling in cultured fibroblasts, and mimic Shh by inducing the differentiation of mesenchymal cells into osteoblasts 21,22. Oxysterols can influence growth and Hh signalling in mouse medulloblastoma cells derived from ptc1 +/ p53 / mice 21. A study in cultured cells has suggested that pro-vitamin D3 or 7-dehydrocholesterol (the immediate precursor of cholesterol) can be pumped out of cells by Ptc to inhibit the activity of Smo in adjacent cells. This study also showed that treatment of zebrafish embryos with high concentrations of pro-vitamin D3 reproduces some phenotypes observed with genetic defects in Hh signalling 23. The non-cell-autonomous effects of vitamin D3 are puzzling in light of the cell-autonomous regulation of Smo by Ptc in flies, but perhaps exogenous provision of vitamin D3 is mimicking an autocrine pathway. Further investigation of the roles oxysterols and vitamin D3 play in Hedgehog pathway may point the way to novel therapeutic opportunities to treat pathway-related cancers: for example, two sterol-synthesis inhibitors in common use, statins and the azole antifungal ketoconazole, can block cell growth and Hh-pathway activity in mouse medulloblastoma cells 21. Current models for Ptc function The simplest model for how Ptc alters the equilibrium between the active and inactive state of Smo is a stoichiometric one, in which Ptc binds and stabilizes the inactive state. This model has been largely abandoned for several reasons. Cross-linking and coimmunoprecipitation experiments have generally failed to confirm an association between Ptc and Smo 24, and live- and fixed-cell fluorescence microscopy has failed to detect significant colocalization of Ptc and Smo 24,25. Most importantly, a 1006 nature cell biology volume 9 number 9 SEPTEMBER 2007
3 stoichiometric model is inconsistent with the observation that Smo is inhibited by Ptc, even when Smo is present at a large molar excess Instead, one molecule of Ptc seems to be able to inhibit several molecules of Smo a property that has been termed catalytic, although no enzymatic activity has been ascribed to Ptc 24. The Ptc amino-acid sequence is distantly related to the bacterial Resistance, Nodulation, Division (RND) family of small-molecule pumps 27. RND pumps are homotrimers, and biochemical and genetic data suggest that Ptc functions as a multimer The RND connection has strengthened the model that Ptc may functions as a pump to change the concentration or localization of a small-molecule second messenger that, in turn, regulates Smo 24. However, mechanisms of Ptc catalytic function other than pumping small molecules, such as the regulation of an intermediate kinase or a G-protein, have not been excluded. These biochemical models of the Ptc Smo interaction must also explain data, mostly from Drosophila, indicating a role for protein localization and stability 1. In many systems, reciprocal changes in the subcellular location of Ptc and Smo have an important role in activation of signalling 25, Without Hh, Ptc cycles between the plasma membrane and internal vesicles, and prevents the movement of Smo from intracellular vesicles to the plasma membrane. Ptc also reduces the levels of Smo protein in cells, perhaps by directing Smo to lysosomes 35. Addition of Hh causes Ptc to be internalized from the plasma membrane, whereas Smo moves in the opposite direction, translocating from cytoplasmic vesicles to the plasma membrane. Genetic inactivation of Ptc causes the constitutive localization of Smo at the plasma membrane, and Smo translocation to the plasma membrane is sufficient for pathway activation 25,34. These findings suggest that Ptc functions by gating the movement of Smo to the plasma membrane. Thus, the active and inactive conformations of Smo suggested by the biochemical analyses may be coupled to protein trafficking events that target Smo to distinct subcellular compartments. The function of Ptc as a regulator of vesicle trafficking is also suggested by the observations that one of the Caenorhabditis elegans Ptc proteins is required for membrane extension during cytokinesis, and that Ptc contains a sterol-sensing domain (SSD) 36. The SSD is a 180 amino-acid module composed of five consecutive transmembrane helices, and is found Model A Cytoplasm Model B Cytoplasm Smo (inactive) Smo (inactive) Oxysterol Oxysterol in proteins that are involved in sterol metabolism or that often mediate sterol-dependent vesicle transport 37. These include the sterol Ptc Shh Shh Smo (active) Smo (active) Cilium Cilium Figure 3 A speculative model for Smo regulation by Ptc and oxysterols. Smo exists in two conformations, an inactive state (red serpentine protein) or an active state (green serpentine protein). Active and inactive Smo proteins are targeted to different subcellular localizations. Inactive Smo is sequestered in vesicles or excluded from ciliary membrane by a barrier at the base of the cilium. Active Smo is transported into cilia where it can activate downstream signalling. Ptc shifts the equilibrium towards inactive Smo, reducing the concentration of active Smo in the cilium. Two models (A and B) for the positive effects of oxysterols are indicated. In model A, oxysterols function as intermediates between Ptc and Smo and stabilize the active state of Smo. Ptc inhibits Smo indirectly by reducing the levels or altering the localization of oxysterols. In model B, oxysterols directly inhibit Ptc function, perhaps by binding to its SSD. Ptc regulatory element-binding protein (SREBP)- cleavage activating protein (SCAP), which mediates transport of SREBP from the nature cell biology volume 9 number 9 SEPTEMBER
4 Pp Ee Rr Ss Pp Ee Cc Tt Ii Vv Ee Focus on DEVELOPMENT AND DISEASE endoplasmic reticulum to the Golgi under low cholesterol conditions, and Niemann-Pick C1 (Npc1) protein, a protein involved in organelle and cholesterol trafficking whose sequence similarity to Ptc extends beyond the SSD 37. Nearly 40% of the mis-sense germline mutations identified in Gorlin s syndrome patients cluster in the Ptc SSD 38. Given these data, and the evidence that sterols regulate the function of Smo, sterol-regulated vesicle trafficking events may have a role in the Ptc Smo interaction. Control of Smo movement by Ptc The seminal discovery that protein components of the primary cilium are required for Hh signalling in vertebrates has focused attention on this organelle as the subcellular location where events in the Hh pathway are coordinated 39,40. The primary cilium a solitary, immotile, cellsurface projection observed on most vertebrate cells functions as a sensory antenna for the detection of optical, mechanical and chemical signals 41. Drosophila cells, except for certain sensory neurons, do not possess cilia, but the functions of cilia in Hedgehog signalling in flies may be performed by another specialized membrane domain at the plasma membrane 35. Many components of the Hh pathway, from Smo to the transcription factors, are located inside the cilium, a tiny ~5 µm structure in fibroblasts Mutations in components of the intraflagellar transport (IFT) apparatus, which transports proteins up and down along the axoneme (the central microtubule-based structure in the cilia), impair Hh signalling in mice and prevent both the activation of proteins and the proteolytic conversion of 3 to its repressor form Smo translocates to the primary cilium when Shh is added to cultured cells (Fig. 2) 43. As SuFu and (components in the pathway downstream of Smo) are located in the primary cilium, this movement would put Smo in the correct location to activate downstream events in the pathway 44. As Hh regulates Ptc activity and Smo localization, Ptc may control Smo in vertebrates by inhibiting its transport to the primary cilium (Fig. 3). This would be analogous to its role in restricting the plasma-membrane localization of Smo in flies. Transport of proteins and lipids to and from the cilium is thought to be gated at its base, although the molecular details of this regulation have not been determined 41,47. Fusion of vesicles carrying Smo from the trans- Golgi with the plasma membrane could be controlled at the ciliary base, and/or there could be regulation of the lateral movement of Smo proteins into the region of the plasma membrane overlying the cilium (Fig. 3). Endogenous Ptc in cultured cells and embryos localizes to both the membrane enveloping the shaft of the cilium, and to a prominent skirt-like domain around the base 48. This places Ptc in precisely the correct location to influence Smo entry into the cilium. Shh is capable of binding Ptc localized in the shaft of the cilium and inducing its disappearance from the cilium, presumably allowing Smo entry 48. This reciprocal movement of Ptc out of the cilium and Smo into the cilium is similar to the observations in flies, where Shh causes Ptc endocytosis and Smo exocytosis. The ability of oxysterols to activate Hh signalling suggests a possible mechanism for how Ptc may regulate Smo localization. Remarkably, the same oxysterols that activate Hh signalling can induce the movement of Smo to the cilium with kinetics identical to that of Shh 48. Epistasis experiments have shown that oxysterols function at the level of Smo, or above, in the pathway 22. As oxysterols do not bind to the cyclopamine-binding site of Smo, they are likely to function either by inactivating Ptc or by functioning at a step between Ptc and Smo to promote Smo movement to the cilium 22. Thus, Ptc may influence the ciliary localization of Smo by controlling the levels or localization of oxysterols (Fig. 3). This speculative hypothesis is attractive because it unites previous ideas about small-molecule, sterol-mediated and trafficking-dependent regulatory mechanisms. This proposed mechanism of Ptc Smo regulation is strongly reminiscent of the regulatory system controlling SREBP, the master transcriptional regulator of cholesterol biosynthetic genes 49. Under cholesterol-rich conditions, oxysterols bind INSIG (an endoplasmic reticulum-resident protein) and cholesterol binds to the previously mentioned SSD-containing protein SCAP, and both binding events promote the interaction between INSIG and SCAP. The INSIG SCAP association keeps the SREBP SCAP complex trapped in the endoplasmic reticulum 50. When sterol levels drop, the INSIG SCAP interaction is abrogated and the SCAP SREBP complex is transported to the Golgi, where a resident protease cleaves and activates SREBP. Thus, sterols are capable of regulating a protein protein interaction that controls a vesicle-trafficking step critical for activation of a transcription factor. In an analogous fashion, oxysterols may promote an unidentified protein protein interaction that favours the movement of Smo to the primary cilium, ultimately leading to activation of the transcription factors. Oxysterols could also affect membrane proteins indirectly, by influencing local membrane fluidity 51. Although the connections between cilia, sterols and Hh signalling promise to yield new insights into some of the long-standing questions in Hh signalling, several important issues remain unresolved. Smo, SuFu and proteins are not located exclusively in the cilia and it remains possible that the cilium-localized pools of these proteins are not relevant to physiological Hh signalling. More importantly, experiments reported to date have only established a correlation, not a causal relationship, between protein localization and Hh-pathway activity. Cilia-dependent and independent modes of Hh signalling could exist that lead to different cellular outcomes. Despite these caveats, deciphering the molecular machinery that controls Smo transport to the primary cilium, and discovering the molecular target of sterols in this process, will shed considerable light on the longstanding question of how Ptc inhibits Smo. The findings promise to provide completely new avenues for modulation of the Hh pathway, creating exciting opportunities in regenerative medicine and cancer treatment. 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