Galectin-3- and phospho-caveolin-1-dependent outside-in integrin signaling mediates the EGF motogenic response in mammary cancer cells.
Galectin-3- and phospho-caveolin-1-dependent outside-in integrin signaling mediates the EGF motogenic response in mammary cancer cells.
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DOI：
10.1091/mbc.e13-02-0095
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发表时间：
2013-07
影响因子：
3.3
通讯作者：
Nabi IR
中科院分区：
文献类型：
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作者：
Boscher C;Nabi IR
与N-聚糖结合的半乳糖凝集素-3促进乳腺癌细胞中EGF受体向整联蛋白的信号传导。这导致磷酸-小窝蛋白-1-，Src-，和ILK-依赖性激活RhoA，导致肌动蛋白重组的圆形背皱褶，细胞迁移和纤连蛋白重塑。在鼠乳腺上皮癌细胞中，半乳糖凝集素-3与β 1，6-乙酰葡糖胺转移酶V（Mgat 5）修饰的N-聚糖结合，限制了质膜中表皮生长因子（EGF）受体的迁移率，并与磷酸小窝蛋白-1协同作用，促进整合素依赖性基质重塑和细胞迁移。我们发现，EGF信号RhoA是半乳糖凝集素-3和磷酸小窝蛋白-1依赖，并促进形成短暂的，肌动蛋白丰富的，圆形背褶（CDR），细胞迁移，和纤连蛋白原纤维通过Src和整合素连接激酶（ILK）依赖的信号。ILK、Src和半乳糖凝集素-3也介导EGF刺激小窝蛋白-1磷酸化。用Mn 2+直接活化整联蛋白诱导半乳糖凝集素-3，ILK和Src依赖性RhoA活化和小窝蛋白-1磷酸化。这表明，在对EGF的反应中，半乳糖凝集素-3能够使由外向内的整合素信号传导刺激磷酸-小窝蛋白-1依赖性RhoA活化、CDR中的肌动蛋白重组、细胞迁移和纤连蛋白重塑。类似地，小窝蛋白-1/半乳糖凝集素-3依赖性EGF信号传导诱导MDA-MB-231人乳腺癌细胞中的运动性、外周肌动蛋白皱褶和RhoA活化，但不诱导HeLa细胞。这些研究定义了半乳糖凝集素-3/磷酸小窝蛋白-1/RhoA信号传导模块，其介导生长因子活化下游的整合素信号传导，导致转移性癌细胞中的肌动蛋白和基质重塑以及肿瘤细胞迁移。
Galectin-3 binding to N-glycans promotes EGF receptor signaling to integrin in mammary cancer cells. This leads to phospho-caveolin-1–, Src-, and ILK-dependent activation of RhoA, resulting in actin reorganization in circular dorsal ruffles, cell migration, and fibronectin remodeling. In murine mammary epithelial cancer cells, galectin-3 binding to β1,6-acetylglucosaminyltransferase V (Mgat5)–modified N-glycans restricts epidermal growth factor (EGF) receptor mobility in the plasma membrane and acts synergistically with phospho-caveolin-1 to promote integrin-dependent matrix remodeling and cell migration. We show that EGF signaling to RhoA is galectin-3 and phospho-caveolin-1 dependent and promotes the formation of transient, actin-rich, circular dorsal ruffles (CDRs), cell migration, and fibronectin fibrillogenesis via Src- and integrin-linked kinase (ILK)–dependent signaling. ILK, Src, and galectin-3 also mediate EGF stimulation of caveolin-1 phosphorylation. Direct activation of integrin with Mn2+ induces galectin-3, ILK, and Src-dependent RhoA activation and caveolin-1 phosphorylation. This suggests that in response to EGF, galectin-3 enables outside-in integrin signaling stimulating phospho-caveolin-1–dependent RhoA activation, actin reorganization in CDRs, cell migration, and fibronectin remodeling. Similarly, caveolin-1/galectin-3–dependent EGF signaling induces motility, peripheral actin ruffling, and RhoA activation in MDA-MB-231 human breast carcinoma cells, but not HeLa cells. These studies define a galectin-3/phospho-caveolin-1/RhoA signaling module that mediates integrin signaling downstream of growth factor activation, leading to actin and matrix remodeling and tumor cell migration in metastatic cancer cells.