Encoding Growth Factor Identity in the Temporal Dynamics of FOXO3 under the Combinatorial Control of ERK and AKT Kinases

Abstract

© 2018 The Authors Extracellular growth factors signal to transcription factors via a limited number of cytoplasmic kinase cascades. It remains unclear how such cascades encode ligand identities and concentrations. In this paper, we use live-cell imaging and statistical modeling to study FOXO3, a transcription factor regulating diverse aspects of cellular physiology that is under combinatorial control. We show that FOXO3 nuclear-to-cytosolic translocation has two temporally distinct phases varying in magnitude with growth factor identity and cell type. These phases comprise synchronous translocation soon after ligand addition followed by an extended back-and-forth shuttling; this shuttling is pulsatile and does not have a characteristic frequency, unlike a simple oscillator. Early and late dynamics are differentially regulated by Akt and ERK and have low mutual information, potentially allowing the two phases to encode different information. In cancer cells in which ERK and Akt are dysregulated by oncogenic mutation, the diversity of states is lower. Eukaryotic transcription factors frequently oscillate between the nucleus and cytosol. We show that translocation by human FOXO3 is pulsatile rather than oscillatory and subject to combinatorial control by the ERK and Akt pathways. As a result, FOXO3 dynamics can encode the identities and concentrations of diverse extracellular growth factors.