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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

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TORC1 coordinates the conversion of Sic1 from a target to an inhibitor of cyclin-CDK-Cks1

Marta Moreno-Torres1, Malika Jaquenoud1, Marie-Pierre Péli-Gulli1

  • 1Department of Biology, University of Fribourg, Fribourg, Switzerland.

Cell Discovery
|May 13, 2017
PubMed

Insights

The target of rapamycin complex 1 (TORC1) pathway regulates cell cycle progression. In yeast, Sic1 stabilization prevents cell division by docking Cks1 and inhibiting cyclin-CDK complexes, a mechanism conserved in proliferating cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Eukaryotic G1-S cell cycle progression is regulated by growth signals via the target of rapamycin complex 1 (TORC1) pathway.
  • TORC1 inactivation in yeast halts G1-S transition by degrading G1 cyclins and stabilizing the Sic1 inhibitor.
  • The stabilization mechanism of Sic1, a cyclin-dependent kinase (CDK) inhibitor, involves Mpk1 phosphorylation and PP2ACdc55 inactivation by greatwall kinase-activated endosulfines.

Purpose of the Study:

  • To elucidate the mechanism by which Sic1 is stabilized in yeast.
  • To investigate the role of Sic1 phosphorylation at Thr173 in regulating its stability.
  • To determine how Sic1 transitions from a target to an inhibitor of cyclin-CDK complexes.

Main Methods:

  • Yeast genetics and molecular biology techniques.
  • Analysis of protein-protein interactions using co-immunoprecipitation.
  • Phosphorylation site analysis and functional assays.

Main Results:

  • The phosphorylated Sic1-Thr173 residue acts as a docking site for Cks1.
  • Sic1 sequesters Clb5-CDK-Cks1 complexes via Cks1 docking and a C-terminal motif, preventing Sic1 degradation.
  • This switch of Sic1 from a target to an inhibitor is conserved in proliferating cells and regulated by greatwall kinase.

Conclusions:

  • Sic1 stabilization is crucial for cell cycle arrest upon TORC1 inactivation.
  • The interaction between Sic1-pThr173 and Cks1 is a key regulatory step.
  • The greatwall kinase integrates cell-cycle and nutritional signals to control Sic1 function and cell proliferation.
Keywords:
CDK inhibitor (CDKI)Cks1G1 cell cycle arrestRim15Sic1cyclin-dependent protein kinase (CDK)greatwall kinase pathwaytarget of rapamycin complex 1 (TORC1)

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