Receptor tyrosine kinases regulate signal transduction through a liquid-liquid phase separated state.
Receptor tyrosine kinases regulate signal transduction through a liquid-liquid phase separated state.
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受体酪氨酸激酶通过液-液分离状态调节信号转导。
DOI：
10.1016/j.molcel.2022.02.005
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发表时间：
2022-03-17
期刊：
影响因子：
16
通讯作者：
Ladbury JE
中科院分区：
文献类型：
--
作者：
Lin CC;Suen KM;Jeffrey PA;Wieteska L;Lidster JA;Bao P;Curd AP;Stainthorp A;Seiler C;Koss H;Miska E;Ahmed Z;Evans SD;Molina-París C;Ladbury JE
信号蛋白募集到激活的受体酪氨酸激酶(RTK)以产生快速、高保真的下游反应，暴露在随机扩散到靶点的模糊性中。液-液相分离(LLP)通过提高所需蛋白质的局部浓度来克服这一点，同时阻碍竞争对手的配体。在这里，我们展示了依赖磷酸化的RTK介导的LLP状态的一个子集。然后，我们研究了由三元复合体组成的相分离液滴的形成，该三元复合体包括RTK(FGFR2)、磷酸酶SHP2和磷脂酶PLCγ1，后者在受体磷酸化后组装。ShP2和激活的PLCγ1通过它们的串联SH2结构域通过先前未描述的接口相互作用。FGFR2和SHP2的复合体结合了激酶和磷酸酶的活性来控制组装的磷酸化状态，同时为活性PLCγ1提供了支架，便于接触其质膜底物。因此，LLP调节RTK信号转导，具有潜在的治疗干预作用。磷酸化的RTK与下游的效应物进行相分离，依赖于磷酸化的多价相互作用驱动FGFR2-SHP2的相分离，FGFR2-SHP2复合体使PLCRTK 1与其质膜底物共定位，酶活性在FGFR2-SHP2-PLCRTK 1的无膜液滴LIN等内部调节。证明磷酸化的RTK在下游蛋白招募时经历液-液相分离。集中在RTK FGFR2，这一过程被证明是调节亚细胞无膜室内的酶活性。
The recruitment of signaling proteins into activated receptor tyrosine kinases (RTKs) to produce rapid, high-fidelity downstream response is exposed to the ambiguity of random diffusion to the target site. Liquid-liquid phase separation (LLPS) overcomes this by providing elevated, localized concentrations of the required proteins while impeding competitor ligands. Here, we show a subset of phosphorylation-dependent RTK-mediated LLPS states. We then investigate the formation of phase-separated droplets comprising a ternary complex including the RTK, (FGFR2); the phosphatase, SHP2; and the phospholipase, PLCγ1, which assembles in response to receptor phosphorylation. SHP2 and activated PLCγ1 interact through their tandem SH2 domains via a previously undescribed interface. The complex of FGFR2 and SHP2 combines kinase and phosphatase activities to control the phosphorylation state of the assembly while providing a scaffold for active PLCγ1 to facilitate access to its plasma membrane substrate. Thus, LLPS modulates RTK signaling, with potential consequences for therapeutic intervention. Phosphorylated RTKs undergo phase separation with downstream effectors Phosphorylation-dependent multivalent interaction drives FGFR2-SHP2 phase separation The FGFR2-SHP2 complex colocalizes PLCγ1 to its plasma membrane substrate Enzymatic activities are regulated within the FGFR2-SHP2-PLCγ1 membraneless droplets Lin et al. demonstrate that phosphorylated RTKs undergo liquid-liquid phase separation upon the recruitment of downstream proteins. Focusing on the RTK FGFR2, this process is shown to modulate enzymatic activities within the subcellular membraneless compartment.
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影响因子：
16
作者：
Hu, JJ;Liu, J;Hubbard, SR
通讯作者：
Hubbard, SR
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20.3
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El-Gamal, Dalia;Williams, Katie;Byrd, John C.
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Byrd, John C.
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作者：
Huculeci, Radu;Garcia-Pino, Abel;van Nuland, Nico
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van Nuland, Nico
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Amaya, Joshua;Ryan, Veronica H.;Fawzi, Nicolas L.
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64.5
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Delarue, M.;Brittingham, G. P.;Pfeffer, S.;Surovtsev, I. V.;Pinglay, S.;Kennedy, K. J.;Schaffer, M.;Gutierrez, J. I.;Sang, D.;Poterewicz, G.;Chung, J. K.;Plitzko, J. M.;Groves, J. T.;Jacobs-Wagner, C.;Engel, B. D.;Holt, L. J.
通讯作者：
Holt, L. J.