RRC ID 61072
Author Miyagi H, Hiroshima M, Sako Y.
Title Cell-to-cell diversification in ERBB-RAS-MAPK signal transduction that produces cell-type specific growth factor responses.
Journal Biosystems
Abstract Growth factors regulate cell fates, including their proliferation, differentiation, survival, and death, according to the cell type. Even when the response to a specific growth factor is deterministic for collective cell behavior, significant levels of fluctuation are often observed between single cells. Statistical analyses of single-cell responses provide insights into the mechanism of cell fate decisions but very little is known about the distributions of the internal states of cells responding to growth factors. Using multi-color immunofluorescent staining, we have here detected the phosphorylation of seven elements in the early response of the ERBB-RAS-MAPK system to two growth factors. Among these seven elements, five were analyzed simultaneously in distinct combinations in the same single cells. Although principle component analysis suggested cell-type and input specific phosphorylation patterns, cell-to-cell fluctuation was large. Mutual information analysis suggested that each cell type uses multitrack (bush-like) signal transduction pathways under conditions in which clear fate changes have been reported. The clustering of single-cell response patterns indicated that the fate change in a cell population correlates with the large entropy of the response, suggesting a bet-hedging strategy is used in decision making. A comparison of true and randomized datasets further indicated that this large variation is not produced by simple reaction noise, but is defined by the properties of the signal-processing network.
Volume 199
Pages 104293
Published 2021-1-1
DOI 10.1016/j.biosystems.2020.104293
PII S0303-2647(20)30170-2
PMID 33221378
MeSH Cell Differentiation / drug effects Cell Line, Tumor Cell Proliferation / drug effects ErbB Receptors / metabolism HeLa Cells Humans Intercellular Signaling Peptides and Proteins / pharmacology* MCF-7 Cells Microscopy, Fluorescence Mitogen-Activated Protein Kinases / metabolism* Models, Biological Phosphorylation / drug effects Principal Component Analysis Signal Transduction / drug effects* Single-Cell Analysis / methods ras Proteins / metabolism*
IF 1.808
Human and Animal Cells HeLa, A431