Abstract

In budding yeast, the mitotic exit network (MEN), a GTPase signaling cascade, integrates spatial and temporal cues to promote exit from mitosis. This signal integration requires transmission of a signal generated on the cytoplasmic face of spindle pole bodies (SPBs; yeast equivalent of centrosomes) to the nucleolus, where the MEN effector protein Cdc14 resides. Here, we show that the MEN activating signal at SPBs is relayed to Cdc14 in the nucleolus through the dynamic localization of its terminal kinase complex Dbf2-Mob1. Cdc15, the protein kinase that activates Dbf2-Mob1 at SPBs, also regulates its nuclear access. Once in the nucleus, priming phosphorylation of Cfi1/Net1, the nucleolar anchor of Cdc14, by the Polo-like kinase Cdc5 targets Dbf2-Mob1 to the nucleolus. Nucleolar Dbf2-Mob1 then phosphorylates Cfi1/Net1 and Cdc14, activating Cdc14. The kinase-primed transmission of the MEN signal from the cytoplasm to the nucleolus exemplifies how signaling cascades can bridge distant inputs and responses.

Highlights

  • In cellular signaling, the sensing of signals and the response often occur in different cellular compartments

  • When the mitotic exit network (MEN) is activated in anaphase, Dbf2-Mob1 is recruited to the outer plaque of spindle pole bodies (SPBs) by binding to Cdc15-phosphorylated Nud1 (Rock et al, 2013)

  • The spatial aspect of signal transmission in the MEN, namely how a signal generated at the outer plaque of the SPBs in the cytosol reaches its target in the nucleolus, was largely unexplored

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Summary

Introduction

The sensing of signals (e.g. binding of signaling molecules at cell surface) and the response (e.g. transcription in the nucleus) often occur in different cellular compartments. The FEAR network promotes dissociation of Cdc from Cfi1/Net by facilitating phosphorylation of Cfi1/Net by mitotic CDKs (Azzam et al, 2004; Queralt et al, 2006) This transient release, not essential for exit from mitosis, is crucial for the timely execution of several anaphase events such as segregation of the nucleolus (D’Amours et al, 2004; Sullivan et al, 2004; TorresRosell et al, 2004) and MEN activation by counteracting CDK inhibition of MEN kinases (Campbell et al, 2019; Jaspersen and Morgan, 2000; Konig et al, 2010). These findings define the molecular mechanisms of crosscompartment signal transmission in the MEN and provide a novel paradigm for how signaling can occur across organelle boundaries

Results
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Discussion
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