Systematic analysis of the MAPK signaling network reveals MAP3K-driven control of cell fate

Amy F Peterson; Kayla Ingram; E J Huang; Jeeun Parksong; Connor McKenney; Gabriel S Bever; Sergi Regot

doi:10.1016/j.cels.2022.10.003

Systematic analysis of the MAPK signaling network reveals MAP3K-driven control of cell fate

Cell Syst. 2022 Nov 16;13(11):885-894.e4. doi: 10.1016/j.cels.2022.10.003. Epub 2022 Nov 9.

Authors

Amy F Peterson¹, Kayla Ingram¹, E J Huang², Jeeun Parksong¹, Connor McKenney¹, Gabriel S Bever³, Sergi Regot⁴

Affiliations

¹ Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Center for Functional Anatomy & Evolution, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Center for Functional Anatomy & Evolution, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: sregot@jhmi.edu.

Abstract

The classic network of mitogen-activated protein kinases (MAPKs) is highly interconnected and controls a diverse array of biological processes. In multicellular eukaryotes, the MAPKs ERK, JNK, and p38 control opposing cell behaviors but are often activated simultaneously, raising questions about how input-output specificity is achieved. Here, we use multiplexed MAPK activity biosensors to investigate how cell fate control emerges from the connectivity and dynamics of the MAPK network. Through chemical and genetic perturbation, we systematically explore the outputs and functions of all the MAP3 kinases encoded in the human genome and show that MAP3Ks control cell fate by triggering unique combinations of MAPK activity. We show that these MAPK activity combinations explain the paradoxical dual role of JNK signaling as pro-apoptotic or pro-proliferative kinase. Overall, our integrative analysis indicates that the MAPK network operates as a unit to control cell fate and shifts the focus from MAPKs to MAP3Ks to better understand signaling-mediated control of cell fate.

Keywords: MAP kinase network; single-cell signaling dynamics.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Humans
JNK Mitogen-Activated Protein Kinases* / metabolism
MAP Kinase Signaling System*
Mitogen-Activated Protein Kinases / metabolism
Phosphorylation
Signal Transduction

Substances

JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases

Grants and funding

R35 GM133499/GM/NIGMS NIH HHS/United States