TY - JOUR
T1 - Discovery of functional interactions among actin regulators by analysis of image fluctuations in an unperturbed motile cell system
AU - Isogai, Tadamoto
AU - Danuser, Gaudenz
N1 - Funding Information:
Work on perturbation-free analysis of actin regulation is funded by the NIH grant no.R01 GM071868 (G.D.). Acknowledgements. We thank Kevin M. Dean and Dana Kim Reed for proof-reading and their comments.
PY - 2018/5/26
Y1 - 2018/5/26
N2 - Cell migration is driven by propulsive forces derived from polymerizing actin that pushes and extends the plasma membrane. The underlying actin network is constantly undergoing adaptation to new mechano-chemical environments and intracellular conditions. As such, mechanisms that regulate actin dynamics inherently contain multiple feedback loops and redundant pathways. Given the highly adaptable nature of such a system, studies that use only perturbation experiments (e.g. knockdowns, overexpression, pharmacological activation/inhibition, etc.) are challenged by the nonlinearity and redundancy of the pathway. In these pathway configurations, perturbation experiments at best describe the function(s) of a molecular component in an adapting (e.g. acutely drug-treated) or fully adapted (e.g. permanent gene silenced) cell system, where the targeted component now resides in a non-native equilibrium. Here, we propose how quantitative live-cell imaging and analysis of constitutive fluctuations of molecular activities can overcome these limitations. We highlight emerging actin filament barbed-end biology as a prime example of a complex, nonlinear molecular process that requires a fluctuation analytic approach, especially in an unperturbed cellular system, to decipher functional interactions of barbed-end regulators, actin polymerization and membrane protrusion. This article is part of the theme issue ‘Self-organization in cell biology’.
AB - Cell migration is driven by propulsive forces derived from polymerizing actin that pushes and extends the plasma membrane. The underlying actin network is constantly undergoing adaptation to new mechano-chemical environments and intracellular conditions. As such, mechanisms that regulate actin dynamics inherently contain multiple feedback loops and redundant pathways. Given the highly adaptable nature of such a system, studies that use only perturbation experiments (e.g. knockdowns, overexpression, pharmacological activation/inhibition, etc.) are challenged by the nonlinearity and redundancy of the pathway. In these pathway configurations, perturbation experiments at best describe the function(s) of a molecular component in an adapting (e.g. acutely drug-treated) or fully adapted (e.g. permanent gene silenced) cell system, where the targeted component now resides in a non-native equilibrium. Here, we propose how quantitative live-cell imaging and analysis of constitutive fluctuations of molecular activities can overcome these limitations. We highlight emerging actin filament barbed-end biology as a prime example of a complex, nonlinear molecular process that requires a fluctuation analytic approach, especially in an unperturbed cellular system, to decipher functional interactions of barbed-end regulators, actin polymerization and membrane protrusion. This article is part of the theme issue ‘Self-organization in cell biology’.
KW - Actin
KW - Fluctuations
KW - Imaging
KW - Real-time
KW - Signalling
KW - System redundancy
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U2 - 10.1098/rstb.2017.0110
DO - 10.1098/rstb.2017.0110
M3 - Article
C2 - 29632262
AN - SCOPUS:85045084305
VL - 373
JO - Philosophical Transactions of the Royal Society B: Biological Sciences
JF - Philosophical Transactions of the Royal Society B: Biological Sciences
SN - 0962-8436
IS - 1747
M1 - 20170110
ER -