title: The full-length unprocessed hedgehog protein is an active signaling molecule.
abstract: The hedgehog (HH) family of ligands plays an important instructional role in metazoan development. HH proteins are initially produced as approximately 45-kDa full-length proteins, which undergo an intramolecular cleavage to generate an amino-terminal product that subsequently becomes cholesterol-modified (HH-Np). It is well accepted that this cholesterol-modified amino-terminal cleavage product is responsible for all HH-dependent signaling events. Contrary to this model we show here that full-length forms of HH proteins are able to traffic to the plasma membrane and participate directly in cell-cell signaling, both in vitro and in vivo. We were also able to rescue a Drosophila eye-specific hh loss of function phenotype by expressing a full-length form of hh that cannot be processed into HH-Np. These results suggest that in some physiological contexts full-length HH proteins may participate directly in HH signaling and that this novel activity of full-length HH may be evolutionarily conserved.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tokhunts
authors.forename: Samer
authors.initials: S
authors.lastname: Singh
authors.forename: Tehyen
authors.initials: T
authors.lastname: Chu
authors.forename: Gisela
authors.initials: G
authors.lastname: D'Angelo
authors.forename: Valerie
authors.initials: V
authors.lastname: Baubet
authors.forename: John A
authors.initials: JA
authors.lastname: Goetz
authors.forename: Zhen
authors.initials: Z
authors.lastname: Huang
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Yuan
authors.forename: Manuel
authors.initials: M
authors.lastname: Ascano
authors.forename: Yana
authors.initials: Y
authors.lastname: Zavros
authors.forename: Pascal P
authors.initials: PP
authors.lastname: Thérond
authors.forename: Sam
authors.initials: S
authors.lastname: Kunes
authors.forename: Nadia
authors.initials: N
authors.lastname: Dahmane
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology; D002642:Chick Embryo; D002645:Chickens; D004330:Drosophila; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016142:Holoprosencephaly / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D016297:Mutagenesis, Site-Directed; D054259:Neural Tube / Q000196:embryology / Q000502:physiology; D000072079:Patched Receptors; D010641:Phenotype; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C509239:SHH protein, human; C077245:hh protein, Drosophila