Author response: Time-resolved multimodal analysis of Src Homology 2 (SH2) domain binding in signaling by receptor tyrosine kinases

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Individual cells in a multicellular organism must receive signals from the environment and from other cells, and adjust their behavior accordingly. Such signals may cause a cell to grow and multiply, move, or even die. Often these signals are received by receptor proteins, which span the cell membrane and thus provide a way for signals from outside the cell to cause changes inside the cell. The tyrosine kinases are one such group of membrane receptors. When a signal binds to a tyrosine kinase, the receptor is activated and it can add chemical tags called phosphates to the part of itself, or a neighboring protein, that is inside the cell. These phosphates provide binding sites for other types of proteins, many of which contain a section called a SH2 domain. This transmits the signal and leads to further changes in the cell. However, there are over a hundred different SH2 domain-containing proteins in human cells and we do not have a clear picture of what exactly happens when receptor tyrosine kinases are activated. Jadwin, Oh et al. have now looked at how the number of SH2 domain binding sites changes over time after a signal is received. The experiments used three different experimental approaches to study a tyrosine kinase called the Epidermal Growth Factor (EGF) receptor, which is often over-active in human cancers. Jadwin, Oh et al. found that the timing of the changes in the number of SH2 domain binding sites on EGF varied widely. The different methods provided different perspectives on exactly when the changes happen, for example, directly observing the binding of SH2 domains to the membrane of living cells under the microscope showed that binding was much slower than expected from other methods that used purified proteins in solutions. This might be due to the receptors taking a relatively long time to form clusters at the membrane after they receive a signal. Further experiments suggested that what happens when EGF is activated may depend not only on the number of SH2 domain binding sites made, but also the timing and the physical arrangement of those sites. A long-term goal for further studies is to understand how various types of signals can lead to different outcomes in the cell.

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