磷酸化
生物
受体酪氨酸激酶
细胞生物学
磷酸酶
蛋白质酪氨酸磷酸酶
信号转导
酪氨酸磷酸化
激酶
支架蛋白
生物化学
作者
Chi-Chuan Lin,Kin Man Suen,Polly-Anne Jeffrey,Lukasz Wieteska,Jessica A Lidster,Peng Bao,Alistair P Curd,Amy Stainthorp,Caroline Seiler,Hans Koss,Eric Miska,Zamal Ahmed,Stephen D Evans,Carmen Molina-París,John E Ladbury
标识
DOI:10.1016/j.molcel.2022.02.005
摘要
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.
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