The circadian E3 ligase complex SCF FBXL3+CRY targets TLK2

We recently demonstrated that the circadian clock component CRY2 is an essential cofactor in the SCF -mediated ubiquitination of c-MYC. Because our demonstration that CRY2 recruits phosphorylated substrates to SCF was unexpected, we investigated the scope of this role by searching for additional sub...

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Bibliographic Details
Published in:Scientific reports 2019-01, Vol.9 (1), p.198
Main Authors: Correia, Stephanie Papp, Chan, Alanna B, Vaughan, Megan, Zolboot, Norjin, Perea, Valerie, Huber, Anne-Laure, Kriebs, Anna, Moresco, James J, Yates, 3rd, John R, Lamia, Katja A
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Circadian Clocks
Cryptochromes - genetics
Cryptochromes - metabolism
F-Box Proteins - metabolism
Humans
Mice
Protein-Serine-Threonine Kinases - drug effects
Protein-Serine-Threonine Kinases - metabolism
Stem Cell Factor - metabolism
Ubiquitin-Protein Ligase Complexes - metabolism
Ubiquitin-Protein Ligases
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Summary:We recently demonstrated that the circadian clock component CRY2 is an essential cofactor in the SCF -mediated ubiquitination of c-MYC. Because our demonstration that CRY2 recruits phosphorylated substrates to SCF was unexpected, we investigated the scope of this role by searching for additional substrates of FBXL3 that require CRY1 or CRY2 as cofactors. Here, we describe an affinity purification mass spectrometry (APMS) screen through which we identified more than one hundred potential substrates of SCF , including the cell cycle regulated Tousled-like kinase, TLK2. Both CRY1 and CRY2 recruit TLK2 to SCF , and TLK2 kinase activity is required for this interaction. Overexpression or genetic deletion of CRY1 and/or CRY2 decreases or enhances TLK2 protein abundance, respectively. These findings reinforce the idea that CRYs function as co-factors for SCF , provide a resource of potential substrates, and establish a molecular connection between the circadian and cell cycle oscillators via CRY-modulated turnover of TLK2.
ISSN:2045-2322