Grb2 Phosphorylation Antagonizes EGFR-driven Ras Activation by Interfering with Condensate Assembly

Henry T Phan, Chun-Wei Lin, Brittany L. Stinger, Joseph B. DeGrandchamp, L.J. Nugent Lew, Serena J. Huang, Jay T Groves
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Abstract

Upon ligand binding, the kinase domain of EGFR phosphorylates multiple tyrosine residues on the receptor cytoplasmic tail through a trans-autophosphorylation process. Phosphotyrosine sites on activated receptors recruit Grb2, which further recruits SOS to initiate downstream signaling by activating Ras. Multivalent binding between SOS and Grb2, as well as direct Grb2:Grb2 interactions, contribute to formation of a protein condensate of activated EGFR. The condensed state of EGFR facilitates autoinhibition release in SOS and exerts regulatory control over signal propagation from activated EGFR to Ras. While kinase activity of EGFR is an essential driver of this signaling process, phosphorylation at residue Y160 on Grb2 blocks Grb2:Grb2 binding and can interfere with EGFR condensation. Here, using a reconstituted system, we examine how titrating kinase activity in the EGFR system can both promote and inhibit signal output to Ras. The results reveal how effects of tyrosine kinase inhibition can, under some circumstances, promote Ras activation by inhibiting negative feedback through Grb2 phosphorylation and disruption of a Grb2 SH2/SH3 dimer interface.
Grb2 磷酸化通过干扰凝结物的组装来拮抗表皮生长因子受体驱动的 Ras 激活
配体结合后,表皮生长因子受体的激酶结构域会通过反式自磷酸化过程使受体胞质尾部的多个酪氨酸残基磷酸化。激活的受体上的磷酸化酪氨酸位点招募 Grb2,后者进一步招募 SOS,通过激活 Ras 启动下游信号传导。SOS 和 Grb2 之间的多价结合,以及 Grb2:Grb2 的直接相互作用,有助于形成活化的表皮生长因子受体的凝集蛋白。表皮生长因子受体的凝集状态有利于 SOS 释放自动抑制,并对活化的表皮生长因子受体向 Ras 的信号传播进行调节控制。表皮生长因子受体的激酶活性是这一信号传导过程的重要驱动力,而 Grb2 上 Y160 残基的磷酸化会阻碍 Grb2:Grb2 的结合,并干扰表皮生长因子受体的凝聚。在这里,我们利用重组系统研究了表皮生长因子受体系统中滴定激酶活性如何促进和抑制向 Ras 的信号输出。结果揭示了酪氨酸激酶抑制作用在某些情况下如何通过抑制 Grb2 磷酸化和破坏 Grb2 SH2/SH3 二聚体界面的负反馈来促进 Ras 激活。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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