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

doi:10.1016/j.isci.2021.102118

Signaling Heterogeneity is Defined by Pathway Architecture and Intercellular Variability in Protein Expression

iScience. 2021 Jan 29;24(2):102118. doi: 10.1016/j.isci.2021.102118. eCollection 2021 Feb 19.

Authors

Dougall Norris^{1

2}, Pengyi Yang^{1

3

4}, Sung-Young Shin^{5

6}, Alison L Kearney^{1

2}, Hani Jieun Kim^{1

3

4}, Thomas Geddes^{1

3

4}, Alistair M Senior^{1

2}, Daniel J Fazakerley¹, Lan K Nguyen^{5

6}, David E James^{1

2

7}, James G Burchfield^{1

2}

Affiliations

¹ Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia.
² School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
³ School of Mathematics and Statistics, The University of Sydney, Sydney, NSW 2006, Australia.
⁴ Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW 2145, Australia.
⁵ Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia.
⁶ Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
⁷ Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.

Abstract

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.

Keywords: Cell Biology; Experimental Models in Systems Biology; Mathematical Biosciences; Systems Biology.