The Drosophila ortholog of the human Wnt inhibitor factor Shifted controls the diffusion of lipid-modified Hedgehog.
The Hedgehog (Hh) family of morphogenetic proteins has important instructional roles in metazoan development and human diseases. Lipid modified Hh is able to migrate to and program cells far away from its site of production despite being associated with membranes. To investigate the Hh spreading mechanism, we characterized Shifted (Shf) as a component in the Drosophila Hh pathway. We show that Shf is the ortholog of the human Wnt inhibitory factor (WIF), a secreted antagonist of the Wingless pathway. In contrast, Shf is required for Hh stability and for lipid-modified Hh diffusion. Shf colocalizes with Hh in the extracellular matrix and interacts with the heparan sulfate proteoglycans (HSPG), leading us to suggest that Shf could provide HSPG specificity for Hh. We also show that human WIF inhibits Wg signaling in Drosophila without affecting the Hh pathway, indicating that different WIF family members might have divergent functions in each pathway.
Gorfinkiel
Nicole
N
Centro de Biología Molecular, Severo Ochoa, C.S.I.C, Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain.
Sierra
Javier
J
Callejo
Ainhoa
A
Ibañez
Carmen
C
Guerrero
Isabel
I
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D004247:DNA / Q000235:genetics; D004058:Diffusion; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000502:physiology; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004843:Epistasis, Genetic; D005260:Female; D017344:Genes, Insect; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013045:Species Specificity; D014921:Wings, Animal / Q000254:growth & development / Q000378:metabolism; D051153:Wnt Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D019812:Heparan Sulfate Proteoglycans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C417258:SHF protein, human; C576538:Shf protein, Drosophila; C485569:WIF1 protein, human; D051153:Wnt Proteins; C077245:hh protein, Drosophila; D004247:DNA