Awasthi Beatrice W, Paulo João A, Burkhart Deborah L, Smith Ian R, Collins Ryan L, Harper J Wade, Gygi Steven P, Haigis Kevin M
Center for Systems Biology, Department of Radiation Oncology, and Center for Cancer Research, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
iScience. 2025 Mar 4;28(4):112146. doi: 10.1016/j.isci.2025.112146. eCollection 2025 Apr 18.
Epidermal growth factor receptor (Egfr)-driven signaling regulates fundamental homeostatic processes. Dysregulated signaling via Egfr is implicated in numerous disease pathologies and distinct Egfr-associated disease etiologies are known to be tissue-specific. The molecular basis of this tissue-specificity remains poorly understood. Most studies of Egfr signaling to date have been performed or in tissue-specific mouse models of disease, which has limited insight into Egfr signaling patterns in healthy tissues. Here, we carried out integrated phosphoproteomic, proteomic, and transcriptomic analyses of signaling changes across various mouse tissues in response to short-term stimulation with the Egfr ligand Egf. We show how both baseline and Egf-stimulated signaling dynamics differ between tissues. Moreover, we propose how baseline phosphorylation and total protein levels may be associated with clinically relevant tissue-specific Egfr-associated phenotypes. Altogether, our analyses illustrate tissue-specific effects of Egf stimulation and highlight potential links between underlying tissue biology and Egfr signaling output.
表皮生长因子受体（Egfr）驱动的信号传导调节基本的稳态过程。通过Egfr的信号失调与多种疾病病理相关，并且已知不同的Egfr相关疾病病因具有组织特异性。这种组织特异性的分子基础仍知之甚少。迄今为止，大多数关于Egfr信号传导的研究都是在疾病的组织特异性小鼠模型中进行的，这限制了我们对健康组织中Egfr信号模式的了解。在这里，我们对各种小鼠组织在受到Egfr配体Egf短期刺激后的信号变化进行了综合磷酸化蛋白质组学、蛋白质组学和转录组学分析。我们展示了不同组织之间基线和Egf刺激的信号动力学如何不同。此外，我们提出了基线磷酸化和总蛋白水平可能如何与临床相关的组织特异性Egfr相关表型相关联。总之，我们的分析阐明了Egf刺激的组织特异性效应，并突出了潜在的组织生物学与Egfr信号输出之间的联系。
