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A module for Rac temporal signal integration revealed with optogenetics.
Brian R Graziano1,2, Delquin Gong1,2, Karen E Anderson3
1Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA.
The Journal of Cell Biology
|July 9, 2017
Summary
Cellular adaptation allows sensing signal changes, not levels. Neutrophil adaptation involves P-Rex1 activating Rac and ArhGAP15 turning it off, revealing key regulators in chemotaxis.
Area of Science:
- Cellular Biology
- Biochemistry
- Signaling Networks
Background:
- Sensory systems adapt to detect changes in stimuli, crucial for cellular functions like directional migration.
- Eukaryotic chemotaxis involves complex signaling networks where adaptation mechanisms are difficult to pinpoint due to feedback and redundancy.
Purpose of the Study:
- To elucidate the specific components and regulators responsible for adaptation in neutrophil chemotactic signaling.
- To dissect the signaling cascade underlying adaptation by probing intermediate nodes.
Main Methods:
- Utilized optogenetics to control intracellular inputs, specifically phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production.
- Employed CRISPR-based knockouts and pharmacological perturbations to identify key proteins.
- Investigated the activation and deactivation dynamics of Rac GTPase.
Main Results:
- Persistent optogenetically driven PIP3 production led to transient Rac activation, a key adaptation feature.
- Identified P-Rex1 as the main PIP3-stimulated Rac activator.
- Demonstrated that actin polymerization and ArhGAP15 are critical for Rac deactivation (turnoff).
Conclusions:
- The study deconstructs neutrophil adaptation, identifying P-Rex1 and ArhGAP15 as key regulators of Rac activity.
- Probing signaling at intermediate nodes, like PIP3-driven Rac activation, is essential to overcome complexity masked by feedback and redundancy in chemotaxis.
