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循环内体中受体酪氨酸激酶之间的相互引发调节细胞信号输出。

Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs.

机构信息

Division of Molecular and Cellular Function, School of Biological Science, Faculty of Biology Medicine and Health (FBMH), The University of Manchester, Manchester, UK.

Division of Cell Matrix and Regenerative Medicine, School of Biological Science, FBMH, The University of Manchester, Manchester, UK.

出版信息

EMBO J. 2021 Jul 15;40(14):e107182. doi: 10.15252/embj.2020107182. Epub 2021 Jun 4.

DOI:10.15252/embj.2020107182
PMID:34086370
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8447605/
Abstract

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.

摘要

整合个体受体酪氨酸激酶（RTKs）下游的信号对于在发育过程中和病理条件下（包括乳腺癌）精细调节细胞内稳态至关重要。然而，信号整合是如何被调节的，以及单个受体的内吞命运是否控制这种信号整合，仍未得到充分阐明。我们结合定量磷酸化蛋白质组学和靶向测定，生成了乳腺癌细胞中依赖于再循环的成纤维细胞生长因子（FGF）信号的详细图片，重点关注不同的 FGF 受体（FGFRs）。我们发现 FGFR 和表皮生长因子（EGF）受体（EGFR）之间存在相互引发作用，这种作用在再循环内体中协调进行。FGFR 再循环配体诱导 EGFR 上苏氨酸 693 的磷酸化。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 上苏氨酸 693 的磷酸化引发 EGF 介导的输出。这种来自再循环内体的不同 RTK 家族之间的相互引发作用是一个新的信号整合枢纽的范例，其中再循环内体协调细胞行为。因此，靶向再循环内体的相互引发作用可能会改善乳腺癌和其他癌症的个体化治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/24f49d775e56/EMBJ-40-e107182-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/1d81fb82530e/EMBJ-40-e107182-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/f5ce1d2eaa8f/EMBJ-40-e107182-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/3ee32e37b0be/EMBJ-40-e107182-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/9c828799cb76/EMBJ-40-e107182-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/596be63d034f/EMBJ-40-e107182-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/56367f2504af/EMBJ-40-e107182-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/79c5bbe8f5d2/EMBJ-40-e107182-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/ee381662e255/EMBJ-40-e107182-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/808c31a21e79/EMBJ-40-e107182-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/24f49d775e56/EMBJ-40-e107182-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/1d81fb82530e/EMBJ-40-e107182-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/f5ce1d2eaa8f/EMBJ-40-e107182-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/3ee32e37b0be/EMBJ-40-e107182-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/9c828799cb76/EMBJ-40-e107182-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/596be63d034f/EMBJ-40-e107182-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/56367f2504af/EMBJ-40-e107182-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/79c5bbe8f5d2/EMBJ-40-e107182-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/ee381662e255/EMBJ-40-e107182-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/808c31a21e79/EMBJ-40-e107182-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c72/8447605/24f49d775e56/EMBJ-40-e107182-g012.jpg

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