Distinct phosphorylations on kinesin costal-2 mediate differential hedgehog signaling strength.
The graded Hedgehog (Hh) signal is transduced by the transmembrane Smoothened (Smo) proteins in both vertebrates and invertebrates. In Drosophila, associations between Smo and the Fused (Fu)/Costal-2 (Cos2)/Cubitus Interruptus (Ci) cytoplasmic complex lead to pathway activation, but it remains unclear how the cytoplasmic complex responds to and transduces different levels of Hh signaling. We show here that, within the Hh gradient field, low- and high-magnitude Smo activations control differentially the phosphorylation of Cos2 on two distinct serines. We also provide evidence that these phosphorylations depend on the Fu kinase activity and lead to a shift of Cos2 distribution from the cytoplasm to the plasma membrane. Moreover, the distinct Cos2 phosphorylation states mediate differential Hh signaling magnitude, suggesting that phosphorylation and relocation of Cos2 to the plasma membrane facilitate high-level Hh signaling through the control of Ci nuclear translocation and transcriptional activity.
CNRS, UMR6543, Institut de Biologie du Développement et du Cancer-IBDC, Nice 06108, France.
Nadia
N
Ranieri
Laurent
L
Ruel
Armel
A
Gallet
Sophie
S
Raisin
Pascal P
PP
Thérond
D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D015533:Transcriptional Activation
D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; C107452:cos protein, Drosophila; C100664:smo protein, Drosophila; C085770:fu protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; C496574:Gprk2 protein, Drosophila; D016547:Kinesins