Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON, M5B 2K3, Canada.
Graduate Program in Molecular Science, Toronto Metropolitan University, Toronto, ON, M5B 2K3, Canada.
J Cell Sci. 2023 Apr 1;136(7). doi: 10.1242/jcs.260133. Epub 2023 Mar 27.
The epidermal growth factor receptor (EGFR) controls many cellular functions. Upon binding its ligand, the receptor undergoes dimerization, phosphorylation and activation of signals including the phosphoinositide-3-kinase (PI3K)-Akt pathway. Although some studies have indicated that EGFR signaling may be controlled by signal enrichment within various membrane rafts, such as flotillin nanodomains, others have found a limited effect of disruption of these nanodomains on EGFR signaling, suggesting that specific factors may define context-specific control of EGFR signaling. Ligand-bound EGFR can homodimerize or instead undergo heterodimerization with the related receptor HER2 (also known as ERBB2) when the latter is expressed. We examined how EGFR signaling in the presence of HER2 distinctly requires flotillin nanodomains. Induction of HER2 expression altered EGFR signaling duration, which is consistent with EGFR-HER2 heterodimer formation. EGFR and c-Src (also known as SRC) localized within plasma membrane structures demarked by flotillin-1 more prominently in HER2-expressing cells. Consistently, HER2-expressing cells, but not cells lacking HER2, were dependent on flotillin-1 and c-Src for EGFR signaling leading to Akt activation and cell proliferation. Hence, HER2 expression establishes a requirement for flotillin membrane rafts and c-Src in EGFR signaling.
表皮生长因子受体 (EGFR) 控制着许多细胞功能。在与其配体结合后，受体发生二聚化、磷酸化，并激活包括磷酸肌醇-3-激酶 (PI3K)-Akt 途径在内的信号通路。尽管一些研究表明，EGFR 信号可能受到各种膜筏（如 flotillin 纳米域）内信号富集的控制，但其他研究发现破坏这些纳米域对 EGFR 信号的影响有限，这表明特定因素可能定义 EGFR 信号的特定上下文控制。当后者表达时，配体结合的 EGFR 可以与相关受体 HER2（也称为 ERBB2）发生同源二聚化或异源二聚化。我们研究了 HER2 存在时 EGFR 信号如何明显需要 flotillin 纳米域。HER2 表达的诱导改变了 EGFR 信号的持续时间，这与 EGFR-HER2 异源二聚体的形成一致。在表达 HER2 的细胞中，EGFR 和 c-Src（也称为 SRC）定位于 flotillin-1 标记的质膜结构中更为明显。一致地，表达 HER2 的细胞而不是缺乏 HER2 的细胞依赖 flotillin-1 和 c-Src 进行 EGFR 信号传导，导致 Akt 激活和细胞增殖。因此，HER2 表达建立了 flotillin 膜筏和 c-Src 在 EGFR 信号传导中的需求。
