The Mitotic Exit Network integrates temporal and spatial signals by distributing regulation across multiple components

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Abstract

GTPase signal transduction pathways control cellular decision making by integrating multiple cellular events into a single signal. The Mitotic Exit Network (MEN), a Ras-like GTPase signaling pathway, integrates spatial and temporal cues to ensure that cytokinesis only occurs after the genome has partitioned between mother and daughter cells during anaphase. Here we show that signal integration does not occur at a single step of the pathway. Rather, sequential components of the pathway are controlled in series by different signals. The spatial signal, nuclear position, regulates the MEN GTPase Tem1. The temporal signal, commencement of anaphase, is mediated by mitotic cyclin-dependent kinase (CDK) phosphorylation of the GTPase's downstream kinases. We propose that integrating multiple signals through sequential steps in the GTPase pathway represents a generalizable principle in GTPase signaling and explains why intracellular signal transmission is a multi-step process. Serial signal integration rather than signal amplification makes multi-step signal transduction necessary.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Ian Winsten Campbell

David H Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Xiaoxue Zhou

David H Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Angelika Amon

David H Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States

For correspondence
angelika@mit.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9837-0314

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD085866)

Angelika Amon

Howard Hughes Medical Institute

Angelika Amon

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.