Abstract
Phosphotyrosine (pTyr) signaling has evolved into a key cell-to-cell communication system. Activated receptor tyrosine kinases (RTKs) initiate several pTyr-dependent signaling networks by creating the docking sites required for the assembly of protein complexes. However, the mechanisms leading to network disassembly and its consequence on signal transduction remain essentially unknown. We show that activated RTKs terminate downstream signaling via the direct phosphorylation of an evolutionarily conserved Tyr present in most SRC homology (SH) 3 domains, which are often part of key hub proteins for RTK-dependent signaling. We demonstrate that the direct EPHA4 RTK phosphorylation of adaptor protein NCK SH3s at these sites results in the collapse of signaling networks and abrogates their function. We also reveal that this negative regulation mechanism is shared by other RTKs. Our findings uncover a conserved mechanism through which RTKs rapidly and reversibly terminate downstream signaling while remaining in a catalytically active state on the plasma membrane.
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•An evolutionarily conserved Tyr is located at the binding interface of SH3 domains•EPHA4 RTK directly phosphorylates NCK adaptor protein SH3 domains on this residue•NCK phosphorylation disrupts its signaling networks and terminates RTK signaling•Other RTK-SH3 effectors pairs share this negative regulatory mechanism
Dionne et al. uncover a mechanism through which receptor tyrosine kinases (RTKs) rapidly and reversibly terminate downstream signaling. The EPHA4 RTK directly phosphorylates an evolutionarily conserved Tyr present in NCK adaptor protein SRC homology (SH) 3 domains, which results in the collapse of signaling networks and abrogates their function.