# Bistability and trigger waves in cell signaling

> **NIH NIH R35** · STANFORD UNIVERSITY · 2021 · $129,628

## Abstract

PROJECT SUMMARY/ABSTRACT
We have been studying cell cycle regulation in Xenopus laevis eggs and extracts, carrying out a combination
of quantitative experiments and modeling to understand how this biological oscillator works and what features
it shares with other regulatory systems. The oscillator circuit includes a positive feedback-based bistable
trigger, which opens the possibility that Cdk1 activity might spread through cytoplasm by what are termed
trigger waves: self-regenerating activity waves, where some active Cdk1 diffuses a small distance and brings
about the activation of the inactive Cdk1 in that volume through the positive feedback, which then diffuses
locally and repeats the process. Action potentials are trigger waves; so are calcium waves, as is the spread of
a fire through a field or the spread of a joke on the internet. We recently showed that both mitosis and
apoptosis spread through Xenopus cytoplasm via trigger waves. We plan to build upon this, and determine:
· What mechanism underpins the ability of interphase Xenopus cytoplasm to self-organize into cell-like
 structures? This was an unexpected observation we made in the course of our apoptosis studies, and it
 is a fascinating phenomenon to try to understand.
· Is the apoptotic control circuit a bistable system? Our discovery of apoptotic trigger waves suggests
 that it is, but others have argued that it may not be. We plan to settle the issue with direct experiments.
· Saltatory vs. continuous mitotic waves. We plan to see whether Cdk1 activation propagates differently
 close to vs. far from the centrosome, where various pro-mitotic proteins concentrate.
· Can bistability restrict signals to certain compartments? Theory tells us that a trigger wave may be
 blocked at the junction between a small tube and a big tube, like a dendrite/axon junction or the base of
 a primary cilium. We plan to carry out experiments with apoptotic trigger waves in microfluidics devices
 to test whether this does occur.
· Do innate immune responses spread via trigger waves? The innate immune system includes positive
 feedback loops, such as interferon-induced interferon release. This could allow cellular defenses to
 spread ahead of an infection in a sheet of cells. We plan to test this possibility experimentally.
· Is there a second mitotic switch? We have found that bistability persists when Cdk1 activity is forced to
 be graded. Our working hypothesis is that double-negative feedback loops centered on PP2A-B55 are
 responsible for this bistability. We are testing this hypothesis with hysteresis experiments in extracts.
· How to proteins that work together stay coordinated as temperature changes, especially in cold-blood
 organisms? Do enzymes that work together have similar activation energies and Q10 values? And/or
 has evolution selected particular circuits that tolerate high degrees of parameter variation?

## Key facts

- **NIH application ID:** 10405348
- **Project number:** 3R35GM131792-03S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** JAMES E. FERRELL
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $129,628
- **Award type:** 3
- **Project period:** 2019-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405348

## Citation

> US National Institutes of Health, RePORTER application 10405348, Bistability and trigger waves in cell signaling (3R35GM131792-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10405348. Licensed CC0.

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