The full-length unprocessed hedgehog protein is an active signaling molecule.
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.
Tokhunts
Robert
R
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Singh
Samer
S
Chu
Tehyen
T
D'Angelo
Gisela
G
Baubet
Valerie
V
Goetz
John A
JA
Huang
Zhen
Z
Yuan
Ziqiang
Z
Ascano
Manuel
M
Zavros
Yana
Y
Thérond
Pascal P
PP
Kunes
Sam
S
Dahmane
Nadia
N
Robbins
David J
DJ
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
D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C509239:SHH protein, human; C077245:hh protein, Drosophila