Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface

This review compares the signaling mechanisms of the Wnt and the Hedgehog proteins. Although Wnts and Hedgehogs are unrelated proteins, they are both modified by lipids, possibly through the action of enzymes that are related to each other. At the surface of target cells, the reception of Wnt and Hedgehog signals is regulated by several molecules, some of which, in particular the Frizzled and Smoothened receptors, are related to each other. Several other aspects of Wnt and Hedgehog transport and signaling are discussed, as well as the possible origin of these pathways.

[1]  P. Ingham,et al.  Role of the Drosophila patched gene in positional signalling , 1991, Nature.

[2]  H. Varmus,et al.  Mutational analysis of mouse Wnt-1 identifies two temperature-sensitive alleles and attributes of Wnt-1 protein essential for transformation of a mammary cell line. , 1992, Molecular biology of the cell.

[3]  N. Perrimon,et al.  Mutations in the segment polarity genes wingless and porcupine impair secretion of the wingless protein. , 1993, The EMBO journal.

[4]  A. M. Arias,et al.  Notch is required for wingless signaling in the epidermis of Drosophila , 1994, Cell.

[5]  J. J. Lee,et al.  Autoproteolysis in hedgehog protein biogenesis. , 1994, Science.

[6]  J. Klingensmith,et al.  Differential requirements for segment polarity genes in wingless signaling , 1995, Mechanisms of Development.

[7]  T. Jessell,et al.  Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis , 1995, Cell.

[8]  P. Beachy,et al.  A potential catalytic site revealed by the 1.7-Å crystal structure of the amino-terminal signalling domain of Sonic hedgehog , 1995, Nature.

[9]  G. Struhl,et al.  Dual Roles for Patched in Sequestering and Transducing Hedgehog , 1996, Cell.

[10]  P. Ingham,et al.  smoothened encodes a receptor-like serpentine protein required for hedgehog signalling , 1996, Nature.

[11]  A. Mccarthy Development , 1996, Current Opinion in Neurobiology.

[12]  G. Struhl,et al.  Direct and Long-Range Action of a Wingless Morphogen Gradient , 1996, Cell.

[13]  Jeremy Nathans,et al.  A new member of the frizzled family from Drosophila functions as a Wingless receptor , 1996, Nature.

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

[15]  M. Noll,et al.  The Drosophila smoothened Gene Encodes a Seven-Pass Membrane Protein, a Putative Receptor for the Hedgehog Signal , 1996, Cell.

[16]  M. Scott,et al.  The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog , 1996, Nature.

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

[18]  N. Perrimon,et al.  The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing. , 1996, Genes & development.

[19]  R. Nusse,et al.  Wnt signaling: a common theme in animal development. , 1997, Genes & development.

[20]  P. Beachy,et al.  Multiple roles of cholesterol in hedgehog protein biogenesis and signaling. , 1997, Cold Spring Harbor symposia on quantitative biology.

[21]  J. Nathans,et al.  A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Scott,et al.  Altered neural cell fates and medulloblastoma in mouse patched mutants. , 1997, Science.

[23]  C. Mello,et al.  Wnt Signaling and an APC-Related Gene Specify Endoderm in Early C. elegans Embryos , 1997, Cell.

[24]  E. Koonin,et al.  Crystal Structure of a Hedgehog Autoprocessing Domain: Homology between Hedgehog and Self-Splicing Proteins , 1997, Cell.

[25]  R. Moon,et al.  Structurally Related Receptors and Antagonists Compete for Secreted Wnt Ligands , 1997, Cell.

[26]  M. Linder,et al.  Signalling functions of protein palmitoylation. , 1998, Biochimica et biophysica acta.

[27]  Q. Gu,et al.  Activating Smoothened mutations in sporadic basal-cell carcinoma , 1998, Nature.

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

[29]  R. Nusse,et al.  Wingless Repression of Drosophila frizzled 2 Expression Shapes the Wingless Morphogen Gradient in the Wing , 1998, Cell.

[30]  C. Niehrs,et al.  Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction , 1998, Nature.

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

[32]  J. Nathans,et al.  Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

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

[34]  K. Ui-Tei,et al.  Dfrizzled-3, a new Drosophila Wnt receptor, acting as an attenuator of Wingless signaling in wingless hypomorphic mutants. , 1999, Development.

[35]  S. Selleck,et al.  The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila , 1999, Nature.

[36]  J. Nathans,et al.  A new secreted protein that binds to Wnt proteins and inhibits their activites , 1999, Nature.

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

[38]  T. Kornberg,et al.  Cytonemes Cellular Processes that Project to the Principal Signaling Center in Drosophila Imaginal Discs , 1999, Cell.

[39]  T. Bouwmeester,et al.  The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals , 1999, Nature.

[40]  N. Perrimon,et al.  Dally cooperates with Drosophila Frizzled 2 to transduce Wingless signalling , 1999, Nature.

[41]  Pao-Tien Chuang,et al.  Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein , 1999, Nature.

[42]  H. Clevers,et al.  Linking Colorectal Cancer to Wnt Signaling , 2000, Cell.

[43]  N. Perrimon,et al.  Role of heparan sulfate proteoglycans in cell-cell signaling in Drosophila. , 2000, Matrix biology : journal of the International Society for Matrix Biology.

[44]  A. McMahon,et al.  More Surprises in the Hedgehog Signaling Pathway , 2000, Cell.

[45]  T. Yakushi,et al.  A new ABC transporter mediating the detachment of lipid-modified proteins from membranes , 2000, Nature Cell Biology.

[46]  M. Freeman Feedback control of intercellular signalling in development , 2000, Nature.

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

[48]  A. Hall,et al.  Axonal Remodeling and Synaptic Differentiation in the Cerebellum Is Regulated by WNT-7a Signaling , 2000, Cell.

[49]  J. Coates,et al.  Adherens junctions and β-catenin-mediated cell signalling in a non-metazoan organism , 2000, Nature.

[50]  Yoichi Kato,et al.  LDL-receptor-related proteins in Wnt signal transduction , 2000, Nature.

[51]  Andrew Tomlinson,et al.  arrow encodes an LDL-receptor-related protein essential for Wingless signalling , 2000, Nature.

[52]  Christoph M. Happel,et al.  WNT signalling molecules act in axis formation in the diploblastic metazoan Hydra , 2000, Nature.

[53]  K. Williams,et al.  Mapping Sonic Hedgehog-Receptor Interactions by Steric Interference* , 2000, The Journal of Biological Chemistry.

[54]  William C. Skarnes,et al.  An LDL-receptor-related protein mediates Wnt signalling in mice , 2000, Nature.

[55]  G. Morata,et al.  The Wingless target gene Dfz3 encodes a new member of the Drosophila Frizzled family , 2000, Mechanisms of Development.

[56]  K. Hofmann A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. , 2000, Trends in biochemical sciences.

[57]  D. Kalderon Transducing the Hedgehog Signal , 2000, Cell.

[58]  M. Bernfield,et al.  Syndecan-1 is required for Wnt-1-induced mammary tumorigenesis in mice , 2000, Nature Genetics.

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

[60]  R. Nusse,et al.  Pathway specificity by the bifunctional receptor frizzled is determined by affinity for wingless. , 2000, Molecular cell.

[61]  S. Prat,et al.  Gibberellins Signal Nuclear Import of PHOR1, a Photoperiod-Responsive Protein with Homology to Drosophila armadillo , 2001, Cell.

[62]  P. Ingham Hedgehog Signaling: A Tale of Two Lipids , 2001, Science.

[63]  J. Nathans,et al.  Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains , 2001, Nature.

[64]  J. Taipale,et al.  The Hedgehog and Wnt signalling pathways in cancer , 2001, Nature.

[65]  S. Eaton,et al.  Argosomes A Potential Vehicle for the Spread of Morphogens through Epithelia , 2001, Cell.

[66]  J Mao,et al.  Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. , 2001, Molecular cell.

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

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

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

[70]  N. Perrimon,et al.  Heparan sulfate proteoglycans are critical for the organization of the extracellular distribution of Wingless. , 2001, Development.

[71]  P. Ingham,et al.  Hedgehog signaling in animal development: paradigms and principles. , 2001, Genes & development.

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

[73]  John B. Thomas,et al.  The Derailed Guidance Receptor Does Not Require Kinase Activity In Vivo , 2001, The Journal of Neuroscience.

[74]  A. McMahon,et al.  Cholesterol Modification of Sonic Hedgehog Is Required for Long-Range Signaling Activity and Effective Modulation of Signaling by Ptc1 , 2001, Cell.

[75]  R. Copley,et al.  HSPG modification by the secreted enzyme Notum shapes the Wingless morphogen gradient. , 2002, Developmental cell.

[76]  T. Kadowaki,et al.  Drosophila Segment Polarity Gene Product Porcupine Stimulates the Posttranslational N-Glycosylation of Wingless in the Endoplasmic Reticulum* , 2002, The Journal of Biological Chemistry.

[77]  D. Kalderon Similarities between the Hedgehog and Wnt signaling pathways. , 2002, Trends in cell biology.

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

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

[80]  N. Perrimon,et al.  The Promise and Perils of Wnt Signaling Through β-Catenin , 2002, Science.

[81]  K. Anderson,et al.  Mouse Dispatched homolog1 Is Required for Long-Range, but Not Juxtacrine, Hh Signaling , 2002, Current Biology.

[82]  N. Perrimon,et al.  The promise and perils of Wnt signaling through beta-catenin. , 2002, Science.

[83]  R. Nusse,et al.  Ligand Receptor Interactions in the Wnt Signaling Pathway inDrosophila * , 2002, The Journal of Biological Chemistry.

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

[85]  Christof Niehrs,et al.  Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. , 2002, Nature.

[86]  Norbert Perrimon,et al.  Heparan sulfate proteoglycan modulation of developmental signaling in Drosophila. , 2002, Biochimica et biophysica acta.

[87]  P. Chuang,et al.  Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling , 2002, Development.

[88]  Christof Niehrs,et al.  Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling , 2002, Nature.

[89]  Satoshi Murakami,et al.  Crystal structure of bacterial multidrug efflux transporter AcrB , 2002, Nature.

[90]  K. Basler,et al.  Wingful, an extracellular feedback inhibitor of Wingless. , 2002, Genes & development.

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

[92]  Alison Rowe,et al.  Wise, a context-dependent activator and inhibitor of Wnt signalling , 2003, Development.

[93]  I. Weissman,et al.  Wnt proteins are lipid-modified and can act as stem cell growth factors , 2003, Nature.

[94]  Lawrence Lum,et al.  Identification of Hedgehog Pathway Components by RNAi in Drosophila Cultured Cells , 2003, Science.

[95]  J. Hsieh,et al.  Mesd Encodes an LRP5/6 Chaperone Essential for Specification of Mouse Embryonic Polarity , 2003, Cell.

[96]  Eric Wieschaus,et al.  Wg/Wnt signal can be transmitted through arrow/LRP5,6 and Axin independently of Zw3/Gsk3beta activity. , 2003, Developmental cell.

[97]  John B. Thomas,et al.  Wnt-mediated axon guidance via the Drosophila Derailed receptor , 2003, Nature.

[98]  R. Mann,et al.  Boca, an Endoplasmic Reticulum Protein Required for Wingless Signaling and Trafficking of LDL Receptor Family Members in Drosophila , 2003, Cell.

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