小柯机器人

美国耶鲁大学医学院Mark A. Lemmon团队近期取得重要工作进展。他们发现胶质母细胞瘤突变会改变EGFR二聚体结构以防止配体偏倚。该项研究成果于2022年2月9日发表在《自然》杂志上。

在这里，研究人员发现常见的细胞外GBM突变阻止了EGFR区分其激活配体。不同的生长因子配体稳定不同的EGFR二聚体结构，这些结构以不同的动力学发出信号来指定或偏向结果。EGF自身会诱导强对称二聚体，这些二聚体会瞬时发出信号促进增殖。上皮调节蛋白(EREG)诱导较弱的不对称二聚体，驱动持续的信号传导和分化。GBM突变降低了EGFR在细胞检测中区分EGREG和EGF的能力，并允许EGFR形成强（EGF样）二聚体以响应EREG和其他低亲和力配体。

使用X射线晶体学，研究人员进一步表明 R84K GBM 突变使EREG驱动的细胞外二聚体对称，因此它们类似于通常在EGF中看到的二聚体。相比之下，第二个GBM突变A265V重塑了关键的二聚化接触，以增强不对称EREG驱动的二聚体。他们的研究结果证明了EGFR在GBM中改变配体识别的重要作用，对治疗靶向具有潜在意义。

据介绍，表皮生长因子受体(epidermal growth factor receptor, EGFR)在人类癌症中经常发生突变，是一个重要的治疗靶点。EGFR抑制剂在肺癌中已取得成功，细胞内酪氨酸激酶结构域的突变激活了受体，但在多形性胶质母细胞瘤(GBM)中却没有成功，因为突变仅发生在细胞外区域。

附：英文原文

Title: Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias

Author: Hu, Chun, Leche, Carlos A., Kiyatkin, Anatoly, Yu, Zhaolong, Stayrook, Steven E., Ferguson, Kathryn M., Lemmon, Mark A.

Issue&Volume: 2022-02-09

Abstract: The epidermal growth factor receptor (EGFR) is frequently mutated in human cancer1,2, and is an important therapeutic target. EGFR inhibitors have been successful in lung cancer, where mutations in the intracellular tyrosine kinase domain activate the receptor1, but not in glioblastoma multiforme (GBM)3, where mutations occur exclusively in the extracellular region. Here we show that common extracellular GBM mutations prevent EGFR from discriminating between its activating ligands4. Different growth factor ligands stabilize distinct EGFR dimer structures5 that signal with different kinetics to specify or bias outcome5,6. EGF itself induces strong symmetric dimers that signal transiently to promote proliferation. Epiregulin (EREG) induces much weaker asymmetric dimers that drive sustained signalling and differentiation5. GBM mutations reduce the ability of EGFR to distinguish EREG from EGF in cellular assays, and allow EGFR to form strong (EGF-like) dimers in response to EREG and other low-affinity ligands. Using X-ray crystallography, we further show that the R84K GBM mutation symmetrizes EREG-driven extracellular dimers so that they resemble dimers normally seen with EGF. By contrast, a second GBM mutation, A265V, remodels key dimerization contacts to strengthen asymmetric EREG-driven dimers. Our results argue for an important role of altered ligand discrimination by EGFR in GBM, with potential implications for therapeutic targeting. Extracellular glioblastoma-associated mutations reduce the ability of the epidermal growth factor receptor to distinguish between its ligands.

DOI: 10.1038/s41586-021-04393-3

Source: https://www.nature.com/articles/s41586-021-04393-3

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