Abstract
Cell division is controlled in part by the timely activation of the CDK, Cdc28, through its association with G1 and G2 cyclins. Cdc28 complexes are regulated in turn by the ubiquitin conjugating enzyme Cdc34 and SCF ubiquitin ligase complexes of the ubiquitin-proteasome system (UPS) to control the initiation of DNA replication. Here we demonstrate that the nutrient sensing kinases PKA and Sch9 phosphorylate S97 of Cdc34. S97 is conserved across species and restricted to the catalytic domain of Cdc34/Ubc7-like E2s. Cdc34-S97 phosphorylation is cell cycle regulated, elevated during active cell growth and division and decreased during cell cycle arrest. Cell growth and cell division are orchestrated to maintain cell size homeostasis over a wide range of nutrient conditions. Cells monitor changes in their environment through nutrient sensing protein kinases. Thus Cdc34 phosphorylation by PKA and Sch9 provides a direct tether between G1 cell division events and cell growth.
Highlights
The ubiquitin proteasome system (UPS) controls cellular functions through the targeted degradation of key regulatory proteins
We demonstrate that Cdc34-S97 phosphorylation is elevated under conditions of active cell growth and division while it is decreased under conditions causing cell cycle arrest
These results provide a direct link between the growth regulating protein kinases PKA and Sch9 and early cell division events through post-translational modification of the ubiquitin-conjugating enzyme Cdc34
Summary
The ubiquitin proteasome system (UPS) controls cellular functions through the targeted degradation of key regulatory proteins. The covalent attachment of ubiquitin often serves as a signal for the degradation of these regulatory proteins by the 26S proteasome (for review see [1]). The first step in ubiquitylation is the formation of a high energy intermediate between ubiquitin and a conserved cysteine of the ubiquitin activating (or E1) enzyme. E1 transfers the ubiquitin via a thiolester linkage to a conserved cysteine of an ubiquitin conjugating (or E2) enzyme. The final transfer of ubiquitin to a specific substrate typically requires both an activated E2 as well as a particular ubiquitin ligase (E3), which provides specific substrate modifying capacity, forming an isopeptide linkage between the COOH-terminal glycine residue of ubiquitin and the e-amino group of a lysine residue of the substrate. A substrate is often targeted for degradation upon the addition of a polyubiquitin chain to the lysine 48 residue of ubiquitin
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