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Which proteins regulate heterogeneous cellular response?

Dec 27, 2016

Koichi Takahashi’s Laboratory for Biochemical Simulation has published a fascinating article in PLOS Computational Biology titled Modeling Cellular Noise Underlying Heterogeneous Cell Responses in the Epidermal Growth Factor Signaling Pathway [1].

Figure showing protein variability and heterogeneity of nuclear ERK

Effects of protein variability on heterogeneity of nuclear ERK shown as coefficient of variation (CV) with (A) low (0.05 ng/mL) and (B) high (50 ng/mL) concentrations of EGF (from Fig 6. [1]).

First author Kazunari Iwamoto described the findings, “ I created a model that could accurately recapitulate experimental results in Epidermal Growth Factor (EGF) signaling pathway, from previously published live cell imaging data [2]. The main finding was that extrinsic noise, due to cell-to-cell variation in protein levels, contributed to cell-to-cell heterogeneity but surprisingly intrinsic noise, from fluctuations in biochemical reactions within the pathway, did not contribute meaningfully to cell heterogeneity.”

“What was particularly surprising,” according to Iwamoto, “was that not all proteins were equally important for variability. The question we were trying to answer was, where does cell heterogeneity come from. In short, the answer was that heterogeneity comes from a few specific proteins. In our model of the EGF signaling pathway, EGFR, Ras, Raf, and MEK proteins had a greater effect on heterogeneity than other proteins,” as depicted in the figure panel A. This is true only in a low concentration of EGF where cells show an all-or-nothing response. On the other hand the effect will not be obvious in a high concentration of EGF where all cells respond to EGF stimulus (panel B).

“I hope that these results can be confirmed by experiments but if we looked at another signaling pathway I would expect to see a similar result where just a few proteins contribute most to cell-to-cell heterogeneity.”

The full article and all Public Library of Science (PLOS) published articles are free and open access for all.

  1. K. Iwamoto, Y. Shindo, and K. Takahashi: "Modeling cellular noise underlying heterogeneous cell responses in the epidermal growth factor signaling pathway" PLoS Compute. Biol. 12(11): e1005222 (2016)
  2. Y. Shindo, K. Iwamoto, K. Mouri, et al.: "Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling" Nat. Commun. 7, Article no.10485 (2016)