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Epidermal growth factor receptors containing a single tyrosine in their C-terminal tail bind different effector molecules and are signaling-competent.
Journal of Biological Chemistry 2017 December 16
The EGF receptor is a classic receptor tyrosine kinase. It contains nine tyrosines in its C-terminal tail, many of which are phosphorylated and bind proteins containing SH2 or phosphotyrosine-binding (PTB) domains. To determine how many and which tyrosines are required to enable EGF receptor-mediated signaling, we generated a series of EGF receptors that contained only one tyrosine in their C-terminal tail. Assays of the signaling capabilities of these single-Tyr EGF receptors indicated that they can activate a range of downstream signaling pathways, including MAP kinase and Akt. The ability of the single-Tyr receptors to signal correlated with their ability to bind Gab1 (Grb2-associated binding protein 1). However, Tyr-992 appeared to be almost uniquely required to observe activation of phospholipase Cγ. These results demonstrate that multiply phosphorylated receptors are not required to support most EGF-stimulated signaling but identify Tyr-992 and its binding partners as a unique node within the network. We also studied the binding of the isolated SH2 domain of Grb2 (growth factor receptor-bound protein 2) and the isolated PTB domain of Shc (SHC adaptor protein) to the EGF receptor. Although these adapter proteins bound readily to wild-type EGF receptor, they bound poorly to the single-Tyr EGF receptors, even those that bound full-length Grb2 and Shc well. This suggests that in addition to pTyr-directed associations, secondary interactions between the tail and regions of the adapter proteins outside of the SH2/PTB domains are important for stabilizing the binding of Grb2 and Shc to the single-Tyr EGF receptors.
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