Signaling diversity enabled by Rap1-regulated plasma membrane ERK with distinct temporal dynamics

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Abstract

A variety of different signals induce specific responses through a common, Extracellular-signal regulated kinase (ERK)-dependent cascade. It has been suggested that signaling specificity can be achieved through precise temporal regulation of ERK activity. Given the wide distrubtion of ERK susbtrates across different subcellular compartments, it is important to understand how ERK activity is temporally regulated at specific subcellular locations. To address this question, we have expanded the toolbox of Förster Resonance Energy Transfer (FRET)-based ERK biosensors by creating a series of improved biosensors targeted to various subcellular regions via sequence specific motifs to measure spatiotemporal changes in ERK activity. Using these sensors, we showed that EGF induces sustained ERK activity near the plasma membrane in sharp contrast to the transient activity observed in the cytoplasm and nucleus. Furthermore, EGF-induced plasma membrane ERK activity involves Rap1, a noncanonical activator, and controls cell morphology and EGF-induced membrane protrusion dynamics. Our work strongly supports that spatial and temporal regulation of ERK activity is integrated to control signaling specificity from a single extracellular signal to multiple cellular processes.

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All data generated and analyzed in this study are included in manuscript and figures.

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Jeremiah Keyes

Department of Pharmacology, University of California, San Diego, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4253-6834
Ambhighainath Ganesan

Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, United States

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The authors declare that no competing interests exist.
Olivia Molinar-Inglis

Department of Pharmacology, University of California, San Diego, La Jolla, United States

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The authors declare that no competing interests exist.
Archer Hamidzadeh

Department of Biomedical Engineering, Yale University, New Haven, United States

Competing interests
The authors declare that no competing interests exist.
Jinfan Zhang

Department of Pharmacology, University of California, San Diego, La Jolla, United States

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The authors declare that no competing interests exist.
Megan Ling

Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United States

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The authors declare that no competing interests exist.
JoAnn Trejo

Department of Pharmacology, University of California, San Diego, La Jolla, United States

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The authors declare that no competing interests exist.
Andre Levchenko

Department of Biomedical Engineering, Yale University, New Haven, United States

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The authors declare that no competing interests exist.
Jin Zhang

Department of Pharmacology, Department of Bioengineering, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, United States

For correspondence
jzhang32@ucsd.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7145-7823

Funding

National Cancer Institute (R35 CA197622)

Jin Zhang

National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK073368)

Jin Zhang

National Institute of General Medical Sciences (K12GM068524)

JoAnn Trejo

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.