Takashi Okada¹, Hiraku Miyagi², Yasushi Sako², Michio Hiroshima^2,3,*, and Atsushi Mochizuki^4,*
(1 RIKEN iTHEMS, 2 RIKEN CPR, 3 RIKEN BDR, 4 Institute for Frontier Life and Medical Sciences, Kyoto University）

Origin of diverse phosphorylation patterns in the ERBB system
Biophysical Journal (2022) DOI：10.1016/j.bpj.2021.12.031

Multicellular organisms exchange signal molecules with each other to achieve coordinated behavior between cells. One group of receptors that receive signal molecules on the cell surface is the ERBB family, which consists of ERBB1, ERBB2, ERBB3, and ERBB4. When signal molecules bind to ERBB molecules, the four types of ERBBs form various dimers, and phosphorylation reactions within dimers occur which triggers a variety of responses of cells, like proliferation or differentiation. In humans, it is known that the distribution (composition) of the amount of four types of ERBB in cells differs depending on the tissue, and it is thought that this creates different behavior for each tissue. However, it was difficult to experimentally measure the details of the binding and phosphorylation reactions of the four ERBBs, so it was not known how various responses to the signals were produced.
To overcome the problem, we conducted experimental measurements using cells with various ERBB compositions and multiple signal molecules, and applied a mathematical model that incorporated all possible reactions of ERBB. First, in the experiment, 7 types of cells with different ERBB compositions were prepared, 2 types of signals were given to each, and the phosphorylation response of 4 types of ERBB was measured. This alone does not reveal the details of the binding reaction and phosphorylation reaction. Therefore, we created a mathematical model that incorporates all possible binding reactions and all phosphorylation reactions between the four ERBB molecules. Then, by comparing with the measurement results, the rate constants of each binding reaction and phosphorylation reaction were determined. In addition, we investigated the effect on the diversity of phosphorylation responses when various rate constants were changed. As a result, it was found that the differences in the phosphorylation reaction rates among the four ERBB molecules has a great effect on the diversity of the response, and the difference in the binding reaction is not a major factor.
It is of great significance to clarify for the first time the essential origin of signal transduction diversity, which was previously unknown. In other words, it can be said that the diversity of cell responses evoked by signal transduction is realized mainly by diversifying the phosphorylation reaction rate in the process of evolution. Based on this research, it may be possible to control the responses of cells caused by signal transduction such as proliferation and differentiation, which may lead to the development of future cancer therapies.

Figure: Identify reaction properties of ERBB receptors and changes of them by signal molecules.