Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2.
The seven-transmembrane protein Smoothened (Smo) transduces extracellular activation of the Hedgehog (Hh) pathway by an unknown mechanism to increase transcriptional activity of the latent cytoplasmic transcription factor Ci (Cubitus interruptus). Here, we present evidence that Smo associates directly with a Ci-containing complex that is scaffolded and stabilized by the atypical kinesin, Costal-2 (Cos2). This complex constitutively suppresses pathway activity, but Hh signaling reverses its regulatory effect to promote Ci-mediated transcription. In response to Hh activation of Smo, Cos2 mediates accumulation and phosphorylation of Smo at the membrane as well as phosphorylation of the cytoplasmic components Fu and Su(fu). Positive response of Cos2 to Hh stimulation requires a portion of the Smo cytoplasmic tail and the Cos2 cargo domain, which interacts directly with Smo.
Lum
Lawrence
L
Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Zhang
Chi
C
Oh
Sekyung
S
Mann
Randall K
RK
von Kessler
Doris P
DP
Taipale
Jussi
J
Weis-Garcia
Frances
F
Gong
Ruoyu
R
Wang
Baolin
B
Beachy
Philip A
PA
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D004628:Embryonic Structures / Q000033:anatomy & histology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D053823:Hedgehog Proteins; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D000072086:Smoothened Receptor; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D046911:Macromolecular Substances; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C491023:SMO protein, human; C490764:SUFU protein, human; D000072086:Smoothened Receptor; C097059:Su(fu) protein, Drosophila; D014157:Transcription Factors; C092937:ci protein, Drosophila; C107452:cos protein, Drosophila; C100664:smo protein, Drosophila; C077245:hh protein, Drosophila; C085770:fu protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D016547:Kinesins