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Abstract
SCF (Skp1-Cullin-F-box) ubiquitin ligases regulate diverse cellular processes including multiple aspects of the cell cycle, transcription, signal transduction, apoptosis, angiogenesis, and cell migration. There are 69 human F-box proteins that function as substrate receptors (SRs) for SCF complexes. The binding of each F-box protein to the core SCF complex produces a unique E3 that targets different subsets of substrates that regulate different cellular pathways. The CAND1 protein is a SR exchange factor for SCF complexes. CAND1 strips off adaptor–SR complexes from the SCF core complex and allows new adapter–SRs to bind to create new active SCF complexes. We have analyzed the SR proteins present in SCF complexes throughout the cell cycle and found systematic changes in SR association with SCF complexes during mitosis. The differences in SCF complexes occur even when the SRs are constitutively present throughout the cell cycle. We show that CAND1 is required to reorganize the diversity of SCF complexes during mitosis. CAND1 is required for the removal of multiple SRs from SCF complexes during mitosis and promoting the integration of a specific SR, FBXW11/-TrCP2, into SCF complexes. Inactivating CAND1/2 causes mitotic arrest that often leads to cell death, and these mitotic defects have been observed in human cells, including HeLa, U2OS, and normal hTERT-derived fibroblasts. These results highlight a novel mechanism by which SCF complexes can undergo large-scale reorganization through a CAND1-dependent process.Folate (vitamin B9) is an essential nutrient that is required for one-carbon metabolism. Emerging evidence indicates that vertebrate folate receptors have functions that do not rely on one-carbon metabolism. We have discovered a novel role for the C. elegans protein FOLR1 in neuronal signaling. We have identified that FOLR-1 expresses in the adult C. elegans NSM neurons, localizing in the two major processes. We also identify GON-2, a calcium channel protein that is required for calcium entry into the NSM neuron upon its activation by adding folate, physically interact with the FOLR-1 protein, and co-localize in the same NSM processes, suggesting a direct mechanism through which FOLR-1 promotes calcium entry during neuronal activation