The capacity of a cell to normally progress through the cell cycle is controlled by complex signaling pathways primarily driven by phosphorylation and ubiquitin-mediated degradation events.
Among the key factors orchestrating cell cycle progression are c
inases or CDKs, which modulate activity and stability of proteins important for cell cycle progression1
. Complementing the activity of CDKs is the a
omplex or c
yclosome (APC/C), a ubiquitin ligase complex responsible for timely- and spatially-coordinated degradation of cell cycle regulators, conferring directionality and irreversibility to cell cycle transitions2, 3
APC/C activity requires Cdc20/fzy or Cdh1/fzr adaptor proteins, which recognize specific motifs in protein substrates such as D- and KEN-boxes4–6
. A timely switch between APC/CCdc20
, which mostly acts during the metaphase-anaphase transition, to APC/CCdh1
, which is activated during exit from mitosis and G1, enables use of the APC/C complex to target different substrates at distinct phases of the cell cycle7
. This switch is controlled by (i) CDK-mediated phosphorylation of APC/C components, including the activating adaptor subunits Cdc20 and Cdh18–11
; (ii) degradation of Cdc20 and Cdh1 through the cell cycle12, 13
; and (iii) temporal expression of several APC/C inhibitors, such as Emi1 or Acm1, during the cell cycle14, 15
Cdh1 phosphorylation by CDKs negatively regulates its ability to activate APC/C during S-phase, G2, and mitosis, when CDKs activity is elevated16–18
. Although it is clear that CDKs target several S/TP motifs in Cdh1, detailed mapping of these phosphoacceptor sites and assessment of their relative importance are lacking19
Here we demonstrate that JNK is activated during G2 and beginning of mitosis. JNK directly phosphorylates human Cdh1 at residues 32, 36, and 151, which inhibit its ability to activate the APC/C during G2, before Cdk1 is readily activated. We further reveal that APC/CCdh1 regulates the stability of nuclear-localized JNK during late mitosis and G1. The significance of this regulation is illustrated by inhibition of JNK degradation during the cell cycle, which results in impaired entry into mitosis and abnormal spindle and chromosomal dynamics.