Multiple roles for lipids in the Hedgehog signalling pathway

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.

[1]  Joseph L. Goldstein,et al.  Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to Insig , 2007, Proceedings of the National Academy of Sciences.

[2]  Jussi Taipale,et al.  Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. , 2002, Genes & development.

[3]  S. Cohen,et al.  Hedgehog Induces Opposite Changes in Turnover and Subcellular Localization of Patched and Smoothened , 2000, Cell.

[4]  M. Gottardis,et al.  Growth-inhibitory effects of vitamin D analogues and retinoids on human pancreatic cancer cells. , 1996, British Journal of Cancer.

[5]  S. Eaton,et al.  Association of Sterol- and Glycosylphosphatidylinositol-linked Proteins with Drosophila Raft Lipid Microdomains* , 1999, The Journal of Biological Chemistry.

[6]  T. Beer,et al.  Calcitriol in the treatment of prostate cancer. , 2006, Anticancer research.

[7]  P. Sánchez,et al.  Gli and hedgehog in cancer: tumours, embryos and stem cells , 2002, Nature Reviews Cancer.

[8]  J. Taipale,et al.  Hedgehog-Mediated Patterning of the Mammalian Embryo Requires Transporter-like Function of Dispatched , 2002, Cell.

[9]  M. Datta,et al.  Sonic Hedgehog signaling in advanced prostate cancer , 2006, Cellular and Molecular Life Sciences CMLS.

[10]  J. Taipale,et al.  Patched acts catalytically to suppress the activity of Smoothened , 2002, Nature.

[11]  E. Koonin,et al.  Molecular Characterization and Developmental Expression of a Retinoid- and Fatty Acid-binding Glycoprotein from Drosophila , 1996, The Journal of Biological Chemistry.

[12]  Y. Yamauchi,et al.  Cholesterol sensing, trafficking, and esterification. , 2006, Annual review of cell and developmental biology.

[13]  L. Piddock Multidrug-resistance efflux pumps ? not just for resistance , 2006, Nature Reviews Microbiology.

[14]  S. Eaton,et al.  Lipoprotein-heparan sulfate interactions in the Hh pathway. , 2007, Developmental cell.

[15]  J. Treisman,et al.  Sightless has homology to transmembrane acyltransferases and is required to generate active Hedgehog protein , 2001, Current Biology.

[16]  J. Adams,et al.  Intracellular vitamin D binding proteins: novel facilitators of vitamin D-directed transactivation. , 2000, Molecular endocrinology.

[17]  Jianchi Feng,et al.  Synergistic and antagonistic roles of the Sonic hedgehog N- and C-terminal lipids , 2004, Development.

[18]  G. R. Brink,et al.  Hedgehog Signaling in Development and Homeostasis of the Gastrointestinal Tract , 2007 .

[19]  Eugene V Koonin,et al.  Hedgehog Patterning Activity: Role of a Lipophilic Modification Mediated by the Carboxy-Terminal Autoprocessing Domain , 1996, Cell.

[20]  L. Ruel,et al.  Cholesterol modification is necessary for controlled planar long-range activity of Hedgehog in Drosophila epithelia , 2006, Development.

[21]  D. Russell,et al.  Oxysterol biosynthetic enzymes. , 2000, Biochimica et biophysica acta.

[22]  L. Nguyen,et al.  Novel regulators of vitamin D action and metabolism: Lessons learned at the Los Angeles zoo , 2003, Journal of cellular biochemistry.

[23]  D. Kalderon The mechanism of hedgehog signal transduction. , 2005, Biochemical Society transactions.

[24]  A. L. Hager-Theodorides,et al.  Sonic hedgehog signalling in T-cell development and activation , 2007, Nature Reviews Immunology.

[25]  James H. Thomas,et al.  NCR-1 and NCR-2, the C. elegans homologs of the human Niemann-Pick type C1 disease protein, function upstream of DAF-9 in the dauer formation pathways , 2004, Development.

[26]  F. F. Weight,et al.  Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith--Lemli--Opitz syndrome. , 2001, Human molecular genetics.

[27]  Suzanne Eaton,et al.  Lipoprotein particles are required for Hedgehog and Wingless signalling , 2005, Nature.

[28]  James M. Olson,et al.  Medulloblastoma Growth Inhibition by Hedgehog Pathway Blockade , 2002, Science.

[29]  H. Wichterle,et al.  Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists , 2002, Journal of biology.

[30]  D. Shouhed,et al.  Oxysterols Regulate Differentiation of Mesenchymal Stem Cells: Pro‐Bone and Anti‐Fat , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[31]  P. Ingham,et al.  Mutations in the Sterol Sensing Domain of Patched suggest a Role for Vesicular Trafficking in Smoothened Regulation , 2001, Current Biology.

[32]  M. Scott,et al.  A Drosophila model of the Niemann-Pick type C lysosome storage disease: dnpc1a is required for molting and sterol homeostasis , 2005, Development.

[33]  S. Nelson,et al.  Oxysterols Are Novel Activators of the Hedgehog Signaling Pathway in Pluripotent Mesenchymal Cells* , 2007, Journal of Biological Chemistry.

[34]  Dennis van Hoof,et al.  Alternative lipid mobilization: The insect shuttle system , 2002, Molecular and Cellular Biochemistry.

[35]  L. Binderup,et al.  Vitamin D receptors and anti-proliferative effects of vitamin D derivatives in human pancreatic carcinoma cells in vivo and in vitro. , 1997, British Journal of Cancer.

[36]  J. Richardson,et al.  Cholesterol substrate pools and steroid hormone levels are normal in the face of mutational inactivation of NPC1 protein Published, JLR Papers in Press, February 3, 2006. , 2006, Journal of Lipid Research.

[37]  L. Nguyen,et al.  Response element binding proteins and intracellular vitamin D binding proteins: novel regulators of vitamin D trafficking, action and metabolism , 2004, The Journal of Steroid Biochemistry and Molecular Biology.

[38]  G. Mitchell,et al.  Hormone-sensitive lipase deficiency in mice causes lipid storage in the adrenal cortex and impaired corticosterone response to corticotropin stimulation. , 2002, Endocrinology.

[39]  Lawrence Lum,et al.  The Hedgehog Response Network: Sensors, Switches, and Routers , 2004, Science.

[40]  D. Peet,et al.  The LXRs: a new class of oxysterol receptors. , 1998, Current opinion in genetics & development.

[41]  J. Welsh,et al.  Functions of 1α,25-dihydroxyvitamin D3 in mammary gland: from normal development to breast cancer , 2001, Steroids.

[42]  H. DeLuca,et al.  Metabolism and mechanism of action of vitamin D. , 1976, Annual review of biochemistry.

[43]  J. Breslow,et al.  Intracellular Cholesterol Transport , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[44]  C. Ambrose,et al.  Identification of a Palmitic Acid-modified Form of Human Sonic hedgehog* , 1998, The Journal of Biological Chemistry.

[45]  J. Strauss,et al.  START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells , 2003, Molecular and Cellular Endocrinology.

[46]  T. Belenkaya,et al.  Drosophila glypicans control the cell-to-cell movement of Hedgehog by a dynamin-independent process , 2004, Development.

[47]  G. Chimini,et al.  efflux of oxysterol by intact cells rapid 25-hydroxycholesterol by membrane vesicles and ABCA1 mediates high-affinity uptake of , 2006 .

[48]  H. Margalit,et al.  Patched 1 Regulates Hedgehog Signaling at the Primary Cilium , 2007 .

[49]  M. Jauhiainen,et al.  The OSBP-related proteins (ORPs): global sterol sensors for co-ordination of cellular lipid metabolism, membrane trafficking and signalling processes? , 2006, Biochemical Society transactions.

[50]  Xin Zeng,et al.  A freely diffusible form of Sonic hedgehog mediates long-range signalling , 2001, Nature.

[51]  T. Willnow,et al.  Pathways for kidney-specific uptake of the steroid hormone 25-hydroxyvitamin D3 , 2002, Current opinion in lipidology.

[52]  W. S. Garver,et al.  The Niemann-Pick C proteins and trafficking of cholesterol through the late endosomal/lysosomal system. , 2002, Current molecular medicine.

[53]  J. Taipale,et al.  A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis , 2003, Nature Genetics.

[54]  L. Ruel,et al.  Cholesterol modification of hedgehog is required for trafficking and movement, revealing an asymmetric cellular response to hedgehog. , 2003, Developmental cell.

[55]  M. Scott,et al.  Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine , 2000, Nature.

[56]  P. Beachy,et al.  Skinny Hedgehog, an Acyltransferase Required for Palmitoylation and Activity of the Hedgehog Signal , 2001, Science.

[57]  N. Ohgami,et al.  Niemann-Pick Type C Disease and Intracellular Cholesterol Trafficking* , 2005, Journal of Biological Chemistry.

[58]  J. Bogerd,et al.  Apolipophorin II/I, Apolipoprotein B, Vitellogenin, and Microsomal Triglyceride Transfer Protein Genes Are Derived from a Common Ancestor , 1999, Journal of Molecular Evolution.

[59]  Jussi Taipale,et al.  Small molecule modulation of Smoothened activity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[60]  M. Scott,et al.  Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[61]  K. Anderson,et al.  Cilia and Hedgehog responsiveness in the mouse. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[62]  G. Fishell,et al.  An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development. , 2001, Developmental biology.

[63]  F. Maxfield,et al.  Lipid and cholesterol trafficking in NPC. , 2004, Biochimica et biophysica acta.

[64]  C. Wetmore,et al.  Sonic hedgehog in normal and neoplastic proliferation: insight gained from human tumors and animal models. , 2003, Current opinion in genetics & development.

[65]  Christian Knaak,et al.  Megalin Functions as an Endocytic Sonic Hedgehog Receptor* , 2002, The Journal of Biological Chemistry.

[66]  P. Beachy,et al.  Teratogen-mediated inhibition of target tissue response to Shh signaling. , 1998, Science.

[67]  D. Kalderon,et al.  Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction , 2005, Nature Cell Biology.

[68]  Yun Zhao,et al.  Hedgehog regulates smoothened activity by inducing a conformational switch , 2007, Nature.

[69]  Alan Carleton,et al.  Sonic hedgehog controls stem cell behavior in the postnatal and adult brain , 2005, Development.

[70]  Tetsuya Tabata,et al.  Three Drosophila EXT genes shape morphogen gradients through synthesis of heparan sulfate proteoglycans , 2004, Development.

[71]  K. Amanai,et al.  Distinct roles of Central missing and Dispatched in sending the Hedgehog signal. , 2001, Development.

[72]  C. Torroja,et al.  Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix , 2006, Development.

[73]  D. Živković,et al.  Repression of Smoothened by Patched-Dependent (Pro-)Vitamin D3 Secretion , 2006, PLoS biology.

[74]  J. Incardona,et al.  Epithelial Trafficking of Sonic Hedgehog by Megalin , 2006, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[75]  G. Fairn,et al.  Emerging roles of the oxysterol-binding protein family in metabolism, transport, and signaling , 2007, Cellular and Molecular Life Sciences.

[76]  F. Kraemer Adrenal cholesterol utilization , 2007, Molecular and Cellular Endocrinology.

[77]  Hongyuan Yang Nonvesicular sterol transport: two protein families and a sterol sensor? , 2006, Trends in cell biology.

[78]  G. Herman,et al.  Inborn errors of sterol biosynthesis. , 2003, Annual review of genomics and human genetics.

[79]  Elina Ikonen,et al.  Cellular cholesterol trafficking and compartmentalization , 2008, Nature Reviews Molecular Cell Biology.

[80]  Y. Ioannou,et al.  Transmembrane molecular pump activity of Niemann-Pick C1 protein. , 2000, Science.

[81]  P. Beachy,et al.  Cholesterol Modification of Hedgehog Signaling Proteins in Animal Development , 1996, Science.

[82]  L. Pallanck,et al.  Mutations of a Drosophila NPC1 Gene Confer Sterol and Ecdysone Metabolic Defects , 2006, Genetics.

[83]  M. Scott,et al.  Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction. , 2003, Genes & development.

[84]  N. Perrimon,et al.  Rasp, a putative transmembrane acyltransferase, is required for Hedgehog signaling. , 2002, Development.

[85]  M. Muenke,et al.  Human developmental disorders and the Sonic hedgehog pathway. , 1998, Molecular medicine today.

[86]  F. Kraemer,et al.  Interaction of Hormone-sensitive Lipase with Steroidogeneic Acute Regulatory Protein , 2003, Journal of Biological Chemistry.

[87]  D K Burns,et al.  Defective forebrain development in mice lacking gp330/megalin. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[88]  R. Kapur,et al.  The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. , 1998, Development.

[89]  C. Chiang,et al.  Cholesterol modification restricts the spread of Shh gradient in the limb bud. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[90]  S. Mellon,et al.  Niemann–Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone , 2004, Nature Medicine.

[91]  L. Lum,et al.  Extensive phosphorylation of Smoothened in Hedgehog pathway activation , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[92]  J. Crowley,et al.  NPC1 and NPC2 Regulate Cellular Cholesterol Homeostasis through Generation of Low Density Lipoprotein Cholesterol-derived Oxysterols* , 2003, Journal of Biological Chemistry.

[93]  L. Malerød,et al.  Oxysterol-activated LXRalpha/RXR induces hSR-BI-promoter activity in hepatoma cells and preadipocytes. , 2002, Biochemical and biophysical research communications.

[94]  M. Scott,et al.  Patched 1 Regulates Hedgehog Signaling at the Primary Cilium , 2022 .

[95]  Shan-Mei Xu,et al.  Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. , 2004, Genes & development.

[96]  F. Porter Human malformation syndromes due to inborn errors of cholesterol synthesis. , 2003, Current opinion in pediatrics.

[97]  N. Perrimon,et al.  Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan. , 1999, Molecular cell.

[98]  K. Anderson,et al.  Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates , 2006, Development.

[99]  J. Pennington,et al.  Lipid storage and mobilization in insects: current status and future directions. , 2001, Insect biochemistry and molecular biology.

[100]  P. Edwards,et al.  Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[101]  S. Azhar,et al.  Cholesterol uptake in adrenal and gonadal tissues: the SR-BI and 'selective' pathway connection. , 2003, Frontiers in bioscience : a journal and virtual library.

[102]  J. Richardson,et al.  Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin. , 2006, The Journal of clinical investigation.

[103]  E. Hafen,et al.  Dispatched, a Novel Sterol-Sensing Domain Protein Dedicated to the Release of Cholesterol-Modified Hedgehog from Signaling Cells , 1999, Cell.

[104]  Yutaka Shimada,et al.  Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours , 2003, Nature.

[105]  I. Paulsen,et al.  Proton-dependent multidrug efflux systems , 1996, Microbiological reviews.

[106]  B. Hollis,et al.  Human plasma transport of vitamin D after its endogenous synthesis. , 1993, The Journal of clinical investigation.

[107]  R. Kapur,et al.  Cyclopamine inhibition of Sonic hedgehog signal transduction is not mediated through effects on cholesterol transport. , 2000, Developmental biology.

[108]  F. Kraemer,et al.  Hormone-sensitive lipase is required for high-density lipoprotein cholesteryl ester-supported adrenal steroidogenesis. , 2004, Molecular endocrinology.