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Direct Phosphorylation of SRC Homology 3 Domains by Tyrosine Kinase Receptors Disassembles Ligand-Induced Signaling Networks

Ugo Dionne 1, 2, 3 François Chartier 3, 2, 1 Yossef López de los Santos 4, 3 Noémie Lavoie 1, 2, 3 David Bernard 4, 3 Sara Banerjee 3, 2, 1 François Otis 1, 3 Kévin Jacquet 1, 2, 3 Michel Tremblay 2 Mani Jain 3, 1 Sylvie Bourassa 2 Gerald Gish 5 Jean-Philippe Gagné 1, 2, 3 Guy Poirier 1, 3, 2 Patrick Laprise 1, 2 Normand Voyer 1, 3 Christian Landry 1, 3 Nicolas Doucet 4, 3 Nicolas Bisson 1, 3, 2
1 Université Laval
2 CHU de Québec–Université Laval
3 PROTEO, The Quebec Network for Research on Protein Function, Engineering, and Applications
4 INRS-IAF - Institut Armand Frappier
5 MSH - Mount Sinai Hospital
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.
Keywords : tyrosine phosphorylation tyrosine kinase receptors EPH receptors adaptor proteins SRC homology domain protein interaction networks proteomics signal transduction
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https://hal-riip.archives-ouvertes.fr/pasteur-01855848
Contributor : Michel Courcelles <>
Submitted on : Wednesday, August 8, 2018 - 4:42:10 PM
Last modification on : Friday, March 27, 2020 - 3:18:04 PM

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Ugo Dionne, François Chartier, Yossef López de los Santos, Noémie Lavoie, David Bernard, et al.. Direct Phosphorylation of SRC Homology 3 Domains by Tyrosine Kinase Receptors Disassembles Ligand-Induced Signaling Networks. Molecular Cell, Elsevier, 2018, 70 (6), pp.995 - 1007.e11. ⟨10.1016/j.molcel.2018.05.013⟩. ⟨pasteur-01855848⟩

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