Low-affinity ligands of the epidermal growth factor receptor are long-range signal transmitters in collective cell migration of epithelial cells.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2024-11-14 DOI:10.1016/j.celrep.2024.114986

Eriko Deguchi, Shuhao Lin, Daiki Hirayama, Kimiya Matsuda, Akira Tanave, Kenta Sumiyama, Shinya Tsukiji, Tetsuhisa Otani, Mikio Furuse, Alexander Sorkin, Michiyuki Matsuda, Kenta Terai

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引用次数: 0

Abstract

Canonical epidermal growth factor (EGF) receptor (EGFR) activation involves the binding of seven EGFR ligands (EGFRLs); however, their extracellular dynamics remain elusive. Here, employing fluorescent probes and a tool for triggering ectodomain shedding, we show that epiregulin (EREG), a low-affinity EGFRL, rapidly and efficiently activates EGFR in Madin-Darby canine kidney (MDCK) epithelial cells and mouse epidermis. During collective cell migration, EGFR and extracellular signal-regulated kinase (ERK) activation waves propagate in an a disintegrin and metalloprotease 17 (ADAM17) sheddase- and EGFRL-dependent manner. Upon induced EGFRL shedding, low-affinity ligands EREG and amphiregulin (AREG) mediate faster and broader ERK waves than high-affinity ligands. Tight/adherens junction integrity is essential for ERK activation propagation, suggesting that tight intercellular spaces prefer the low-affinity EGFRLs for efficient signal transmission. In EREG-deficient mice, ERK wave propagation and cell migration were impaired during skin wound repair. We additionally show that heparin-binding EGF-like growth factor (HBEGF) primarily promotes surrounding cell motility. Our findings underscore the pivotal role of low-affinity EGFRLs in rapid intercellular signal transmission.

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表皮生长因子受体的低亲和性配体是上皮细胞集体迁移过程中的长程信号传递者。

典型表皮生长因子（EGF）受体（EGFR）的活化涉及七种表皮生长因子受体配体（EGFRLs）的结合；然而，它们在细胞外的动态变化仍然难以捉摸。在这里，我们利用荧光探针和一种触发外显子脱落的工具，证明表皮生长因子受体配体（epiregulin，EREG）是一种低亲和力的表皮生长因子受体配体，它能快速有效地激活Madin-Darby犬肾（MDCK）上皮细胞和小鼠表皮中的表皮生长因子受体。在细胞集体迁移过程中，表皮生长因子受体（EGFR）和细胞外信号调节激酶（ERK）激活波以崩解酶和金属蛋白酶17（ADAM17）脱落酶和表皮生长因子受体依赖的方式传播。在诱导表皮生长因子淋巴细胞脱落时，低亲和力配体EREG和两性胰蛋白酶（AREG）比高亲和力配体更快、更广泛地介导ERK波。紧密/粘连连接的完整性对ERK激活的传播至关重要，这表明紧密的细胞间隙更喜欢低亲和力的表皮生长因子淋巴因子，以实现有效的信号传输。在EREG缺陷的小鼠中，ERK波的传播和细胞迁移在皮肤伤口修复过程中受损。我们还发现，肝素结合型表皮生长因子样生长因子（HBEGF）主要促进周围细胞的运动。我们的发现强调了低亲和性表皮生长因子淋巴因子在细胞间信号快速传递中的关键作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.