Origin of diverse phosphorylation patterns in the ERBB system

Intercellular signals induce various cellular responses, including growth, proliferation, and differentiation, via the dynamic processes of signal transduction pathways. For cell-fate decisions, ligand-binding induces the phosphorylation of ERBB receptors, which in turn activate downstream molecules. The ERBB family includes four subtypes, which diverged through two gene duplications from a common ancestor, of different kinetic properties. Differences in the expression patterns of the subtypes have been reported between different organs in the human body. However, how these different kinetic and expression properties influence the diverse phosphorylation dynamics of ERBB proteins is not well understood. Here we study the phosphorylation dynamics by experimental and mathematical analyses. The experimental measurements clarified that the phosphorylation dynamics heavily depend on the ERBB expression profiles. We developed a mathematical model consisting of the four subtypes as monomers, homodimers and heterodimers and estimated the rate constants governing the phosphorylation dynamics from the experimental data. To understand the origin of the diversity of the phosphorylation responses of the ERBB system, we analyzed the expression profiles and reaction rates of the ERBB subtypes. The difference in phosphorylation rates between ERBB subtypes showed a much larger contribution to the diversity of the phosphorylation responses than did the dimerization rates. This result implies that divergent evolution in phosphorylation reactions rather than in dimerization reactions after whole genome duplications was essential for increasing the diversity of the phosphorylation responses. Statement of Significance It is known that the expression patterns of a protein family are different between different organs in the human body. This difference is considered essential for the functional diversity between organs. However, the dynamical processes that translate expression patterns into function are not well understood. Here we study the origin of the diversity in ERBB phosphorylation patterns by combining experimental and mathematical methods. We confirmed experimentally that phosphorylation patterns depend on the ERBB expression profiles. Our mathematical model found that differences in phosphorylation rates made the largest contribution to the diversity of phosphorylation patterns between ERBB subtypes.