title: Lipid modifications of Sonic hedgehog ligand dictate cellular reception and signal response.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors: Vandana K
authors: VK
authors: Grover
authors: J Gerardo
authors: JG
authors: Valadez
authors: Aaron B
authors: AB
authors: Bowman
authors: Michael K
authors: MK
authors: Cooper
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D053823:Hedgehog Proteins / Q000737:chemistry / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D050356:Lipid Metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D008024:Ligands; D002784:Cholesterol