Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs.
Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs.
复制标题
DOI：
10.15252/embj.2020107182
复制
发表时间：
2021-07-15
期刊：
影响因子：
--
通讯作者：
Francavilla C
中科院分区：
文献类型：
--
作者：
Smith MP;Ferguson HR;Ferguson J;Zindy E;Kowalczyk KM;Kedward T;Bates C;Parsons J;Watson J;Chandler S;Fullwood P;Warwood S;Knight D;Clarke RB;Francavilla C
个体受体酪氨酸激酶（RTK）下游信号传导的整合对于在发育期间和病理条件（包括乳腺癌）中微调细胞稳态至关重要。然而，信号整合是如何调节的，以及单个受体的内吞命运是否控制这种信号整合仍然很难阐明。结合定量磷酸蛋白质组学和靶向测定，我们生成了乳腺癌细胞中循环依赖性成纤维细胞生长因子（FGF）信号传导的详细图像，重点关注不同的FGF受体（FGFR）。我们发现了FGFR和表皮生长因子（EGF）受体（EGFR）之间的相互启动，这是协调再循环内体。FGFR再循环配体诱导苏氨酸693上的EGFR磷酸化。这种磷酸化事件改变了FGFR和EGFR的运输，并引发FGFR介导的增殖，但不引发细胞侵袭。反过来，FGFR信号通过EGFR苏氨酸693磷酸化引发EGF介导的输出。来自再循环内体的不同RTK家族之间的这种相互引发证实了一种新的信号传导整合枢纽，其中再循环内体协调细胞行为。因此，靶向个体受体的相互启动可能会改善乳腺癌和其他癌症的个性化治疗。磷酸化蛋白质组学揭示，FGFR再循环配体诱导特异性EGFR磷酸化，这反过来改变乳腺癌细胞中FGFR2b的运输和信号传导。
Integration of signalling downstream of individual receptor tyrosine kinases (RTKs) is crucial to fine‐tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration remains poorly elucidated. Combining quantitative phosphoproteomics and targeted assays, we generated a detailed picture of recycling‐dependent fibroblast growth factor (FGF) signalling in breast cancer cells, with a focus on distinct FGF receptors (FGFRs). We discovered reciprocal priming between FGFRs and epidermal growth factor (EGF) receptor (EGFR) that is coordinated at recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR‐mediated proliferation but not cell invasion. In turn, FGFR signalling primes EGF‐mediated outputs via EGFR threonine 693 phosphorylation. This reciprocal priming between distinct families of RTKs from recycling endosomes exemplifies a novel signalling integration hub where recycling endosomes orchestrate cellular behaviour. Therefore, targeting reciprocal priming over individual receptors may improve personalized therapies in breast and other cancers. Phosphoproteomics reveal that FGFR recycling ligands induce specific EGFR phosphorylation that in turn alters FGFR2b trafficking and signaling in breast cancer cells.