Signaling Heterogeneity is Defined by Pathway Architecture and Intercellular Variability in Protein Expression
Dougall Norris,
Pengyi Yang,
Sung-Young Shin,
Alison L. Kearney,
Hani Jieun Kim,
Thomas Geddes,
Alistair M. Senior,
Daniel J. Fazakerley,
Lan K. Nguyen,
David E. James,
James G. Burchfield
Affiliations
Dougall Norris
Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia
Pengyi Yang
Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; School of Mathematics and Statistics, The University of Sydney, Sydney, NSW 2006, Australia; Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia
Sung-Young Shin
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia; Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Alison L. Kearney
Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia
Hani Jieun Kim
Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; School of Mathematics and Statistics, The University of Sydney, Sydney, NSW 2006, Australia; Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia
Thomas Geddes
Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; School of Mathematics and Statistics, The University of Sydney, Sydney, NSW 2006, Australia; Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia
Alistair M. Senior
Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia
Daniel J. Fazakerley
Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia
Lan K. Nguyen
Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia; Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Corresponding author
David E. James
Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia; Corresponding author
James G. Burchfield
Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia; Corresponding author
Summary: Insulin's activation of PI3K/Akt signaling, stimulates glucose uptake by enhancing delivery of GLUT4 to the cell surface. Here we examined the origins of intercellular heterogeneity in insulin signaling. Akt activation alone accounted for ~25% of the variance in GLUT4, indicating that additional sources of variance exist. The Akt and GLUT4 responses were highly reproducible within the same cell, suggesting the variance is between cells (extrinsic) and not within cells (intrinsic). Generalized mechanistic models (supported by experimental observations) demonstrated that the correlation between the steady-state levels of two measured signaling processes decreases with increasing distance from each other and that intercellular variation in protein expression (as an example of extrinsic variance) is sufficient to account for the variance in and between Akt and GLUT4. Thus, the response of a population to insulin signaling is underpinned by considerable single-cell heterogeneity that is largely driven by variance in gene/protein expression between cells.
