Distinct protein degradation mechanisms mediated by Cul1 and Cul3 controlling Ci stability in Drosophila eye development.
The ubiquitin-like protein, Nedd8, covalently modifies members of the Cullin family. Cullins are the major components of a series of ubiquitin ligases that control the degradation of a broad range of proteins. We found that Nedd8 modifies Cul1 in Drosophila. In Drosophila Nedd8 and Cul1 mutants, protein levels of the signal transduction effectors, Cubitus interruptus (Ci) and Armadillo (Arm), and the cell cycle regulator, Cyclin E (CycE), are highly accumulated, suggesting that the Cul1-based SCF complex requires Nedd8 modification for the degradation processes of Ci, Arm, and CycE in vivo. We further show that two distinct degradation mechanisms modulating Ci stability in the developing eye disc are separated by the morphogenetic furrow (MF) in which retinal differentiation is initiated. In cells anterior to the MF, Ci proteolytic processing promoted by PKA requires the activity of the Nedd8-modified Cul1-based SCF(Slimb) complex. In posterior cells, Ci degradation is controlled by a mechanism that requires the activity of Cul3, another member of the Cullin family. This posterior Ci degradation mechanism, which partially requires Nedd8 modification, is activated by Hedgehog (Hh) signaling and is PKA-independent.
Ou
Chan-Yen
CY
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Lin
Yi-Fan
YF
Chen
Ying-Jiun
YJ
Chien
Cheng-Ting
CT
D000595:Amino Acid Sequence; D000818:Animals; D051186:Armadillo Domain Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D044842:Cullin Proteins; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005123:Eye / Q000254:growth & development / Q000378:metabolism; D017344:Genes, Insect; D053823:Hedgehog Proteins; D019476:Insect Proteins / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D000075687:NEDD8 Protein; D009687:Nuclear Proteins; D011499:Protein Processing, Post-Translational; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014157:Transcription Factors; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
C495305:ARM protein, Drosophila; D051186:Armadillo Domain Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C503647:Cul3 protein, Drosophila; C100318:Cullin 1; D044842:Cullin Proteins; D019927:Cyclin E; C115373:DNA supercoiling factor, Drosophila; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D019476:Insect Proteins; D000075687:NEDD8 Protein; C513173:Nedd8 protein, Drosophila; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014157:Transcription Factors; D014452:Ubiquitins; C092937:ci protein, Drosophila; C100664:smo protein, Drosophila; C077245:hh protein, Drosophila; D017868:Cyclic AMP-Dependent Protein Kinases