Abstract
Eukaryotic cell cycle progression through G1–S is driven by hormonal and growth-related signals that are transmitted by the target of rapamycin complex 1 (TORC1) pathway. In yeast, inactivation of TORC1 restricts G1–S transition due to the rapid clearance of G1 cyclins (Cln) and the stabilization of the B-type cyclin (Clb) cyclin-dependent kinase (CDK) inhibitor Sic1. The latter mechanism remains mysterious but requires the phosphorylation of Sic1-Thr173 by Mpk1 and inactivation of the Sic1-pThr173-targeting phosphatase (PP2ACdc55) through greatwall kinase-activated endosulfines. Here we show that the Sic1-pThr173 residue serves as a specific docking site for the CDK phospho-acceptor subunit Cks1 that sequesters, together with a C-terminal Clb5-binding motif in Sic1, Clb5-CDK-Cks1 complexes, thereby preventing them from flagging Sic1 for ubiquitin-dependent proteolysis. Interestingly, this functional switch of Sic1 from a target to an inhibitor of cyclin-CDK-Cks1 also operates in proliferating cells and is coordinated by the greatwall kinase, which responds to both Cln-CDK-dependent cell-cycle and TORC1-mediated nutritional cues.
Highlights
Eukaryotic cell proliferation requires proper coordination of growth with key cell cycle events such as the G1–S cell cycle transition, which is coined START in yeast [1]
Phosphorylation of Sic1-Thr173 is essential for Sic1 to escape cyclin-dependent kinase (CDK)-mediated, N-terminal multi-phosphorylation upon target of rapamycin complex 1 (TORC1) inactivation
We first compared on phos-tag gels the phosphorylation levels of Sic1 and Sic1T173A from rapamycin-treated cdc4-2ts strains, which were preincubated at the restrictive temperature to inactivate Cdc4 and block SCFCdc4mediated degradation of the Sic1 variants
Summary
Eukaryotic cell proliferation requires proper coordination of growth with key cell cycle events such as the G1–S cell cycle transition, which is coined START in yeast [1]. To elucidate why rapamycin-treated sic1T173A cells exhibit enhanced Cln- and/or Clb-CDK activity, we analyzed whether the mutation of Thr173 in Sic1 indirectly affected the levels of G1- (Cln1/2) or S-phase
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