Multiple roles for lipids in the Hedgehog signalling pathway

Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 07/2008; 9(6):437-45. DOI: 10.1038/nrm2414
Source: PubMed


The identification of endogenous sterol derivatives that modulate the Hedgehog (Hh) signalling pathway has begun to suggest testable hypotheses for the cellular biological functions of Patched, and for the lipoprotein association of Hh. Progress in the field of intracellular sterol trafficking has emphasized how tightly the distribution of intracellular sterol is controlled, and suggests that the synthesis of sterol derivatives can be influenced by specific sterol-delivery pathways. The combination of this field with Hh studies will rapidly give us a more sophisticated understanding of both the Hh signal-transduction pathway and the cell biology of sterol metabolism.

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Available from: Suzanne Eaton,
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    • "A key question in the study of Hh signal transduction concerns the physiological mechanisms that influence Smo activity in pathway-responsive cells. One leading model hypothesizes that Smo is regulated by an endogenous lipidic modulator whose availability is controlled by Ptch1 transport activity (Eaton, 2008; Hausmann et al., 2009; Taipale et al., 2002). Indeed, a remarkable array of exogenous small molecules impinges on vertebrate Smo, including the plant-derived sterol cyclopamine and its synthetic mimics (Chen et al., 2002a, 2002b), which are finding therapeutic uses as pathway antagonists (Von Hoff et al., 2009; Rudin et al., 2009; Tang et al., 2012; Teglund and Toftgå rd, 2010). "
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    ABSTRACT: Hedgehog (Hh) signaling during development and in postembryonic tissues requires activation of the 7TM oncoprotein Smoothened (Smo) by mechanisms that may involve endogenous lipidic modulators. Exogenous Smo ligands previously identified include the plant sterol cyclopamine (and its therapeutically useful synthetic mimics) and hydroxylated cholesterol derivatives (oxysterols); Smo is also highly sensitive to cellular sterol levels. The relationships between these effects are unclear because the relevant Smo structural determinants are unknown. We identify the conserved extracellular cysteine-rich domain (CRD) as the site of action for oxysterols on Smo, involving residues structurally analogous to those contacting the Wnt lipid adduct in the homologous Frizzled CRD; this modulatory effect is distinct from that of cyclopamine mimics, from Hh-mediated regulation, and from the permissive action of cellular sterol pools. These results imply that Hh pathway activity is sensitive to lipid binding at several Smo sites, suggesting mechanisms for tuning by multiple physiological inputs.
    Developmental Cell 08/2013; 26(4). DOI:10.1016/j.devcel.2013.07.015 · 9.71 Impact Factor
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    • "In order to act on cells at a distance from the producing cell, these signaling molecules have to move through a hydrophilic environment. Formation of oligomers (B) and lipoprotein particles (C) are thought to mask hydrophobic residues or modifications and have been implicated in the transport of hydrophobic signals such as Hh and Wg. Figure modified from (Eaton 2008). "
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    ABSTRACT: Extracellular signaling molecules have crucial roles in development and homeostasis, and their incorrect deployment can lead to developmental defects and disease states. Signaling molecules are released from sending cells, travel to target cells, and act over length scales of several orders of magnitude, from morphogen-mediated patterning of small developmental fields to hormonal signaling throughout the organism. We discuss how signals are modified and assembled for transport, which routes they take to reach their targets, and how their range is affected by mobility and stability.
    Developmental Cell 07/2011; 21(1):145-58. DOI:10.1016/j.devcel.2011.06.001 · 9.71 Impact Factor
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    • "Hedgehog proteins are among several secreted signaling proteins that are covalently modified by lipid moieties (Reviewed in [45]). Hedgehog family members are the only proteins that are known to be modified by cholesterol [11], and this discovery cultivated attention on the influences of lipids on morphogen signaling (Reviewed in [46]). The influences of the lipid modification on ligand release and association with multivalent particles have been well characterized [8], [10], [15], [19], [20]. "
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    ABSTRACT: Sonic hedgehog (Shh) signaling regulates cell growth during embryonic development, tissue homeostasis and tumorigenesis. Concentration-dependent cellular responses to secreted Shh protein are essential for tissue patterning. Shh ligand is covalently modified by two lipid moieties, cholesterol and palmitate, and their hydrophobic properties are known to govern the cellular release and formation of soluble multimeric Shh complexes. However, the influences of the lipid moieties on cellular reception and signal response are not well understood. We analyzed fully lipidated Shh and mutant forms to eliminate one or both adducts in NIH3T3 mouse embryonic fibroblasts. Quantitative measurements of recombinant Shh protein concentration, cellular localization, and signaling potency were integrated to determine the contributions of each lipid adduct on ligand cellular localization and signaling potency. We demonstrate that lipid modification is required for cell reception, that either adduct is sufficient to confer cellular association, that the cholesterol adduct anchors ligand to the plasma membrane and that the palmitate adduct augments ligand internalization. We further show that signaling potency correlates directly with cellular concentration of Shh ligand. The findings of this study demonstrate that lipid modification of Shh determines cell concentration and potency, revealing complementary functions of hydrophobic modification in morphogen signaling by attenuating cellular release and augmenting reception of Shh protein in target tissues.
    PLoS ONE 07/2011; 6(7):e21353. DOI:10.1371/journal.pone.0021353 · 3.23 Impact Factor
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