Galectin-3 carbohydrate recognition domain induces microvascular endothelial cell migration by activating β1 Integrin
Galectin-3 carbohydrate recognition domain induces microvascular endothelial cell migration by activating β1 Integrin
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Galectin-3 碳水化合物识别域通过激活 β1 整合素诱导微血管内皮细胞迁移
DOI：
10.18632/oncotarget.24155
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发表时间：
2018-01
期刊：
影响因子：
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通讯作者：
Guihua Tai
中科院分区：
文献类型：
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作者：
Zhongyu Zhang;Yuan Guan;Xiyao Yu;Hairong Cheng;Yifa Zhou;Guihua Tai
半乳糖凝集素-3(Galectin-3，Gal-3)由一个长的N-末端(NT)连接到其保守的碳水化合物识别结构域(CRD)上。NT被基质金属蛋白酶和前列腺特异性抗原降解。在这里，我们证明了缺失前12个或68个残基或完整110个残基的NT截短的Gal-3变体可触发人微血管内皮细胞(HMEC-1)的迁移。通过质谱分析和下拉分析，我们发现Gal-3CRD结合并激活了细胞表面的β-1整合素，促进了FAK的磷酸化。抗体阻断实验表明α-2、α-4和α-6整合素参与其中，α-2和β-1形成异源二聚体。短发夹状RNA敲除或抗体介导的β1整合素功能抑制可抑制CRD诱导的细胞迁移并减弱其磷酸化。FAK特异性抑制剂也能抑制Gal-3CRD诱导的细胞迁移。有趣的是，全长Gal-3和它的CRD促进了类似的作用。这些发现强调了在制定应对肿瘤血管生成的策略时重新考虑Gal-3NT裂解的必要性。
Galectin-3 (Gal-3) is composed of a long N-terminal tail (NT) connected to its conserved carbohydrate recognition domain (CRD). The NT is degraded by matrix metalloproteinases and prostate-specific antigen. Here, we demonstrate that NTtruncated Gal-3 variants with deletion of the first 12 or 68 residues, or the entire 110-residues NT, triggers migration of human microvascular endothelial cells (HMEC-1). Using mass spectrometry and pull-down analysis, we show that the Gal-3 CRD binds to and activates cell surface β1 integrin promoting phosphorylation of FAK. Antibody blocking assays suggested that α2, α4, and α6 integrins are involved, with α2 and β1 forming a heterodimer. shRNA knockdown or antibody-mediated inhibition of β1 integrin function inhibited CRD-induced cell migration and attenuated FAK phosphorylation. FAK-specific inhibitors also inhibited Gal-3 CRD-induced cell migration. Interestingly, full-length Gal-3 and its CRD promoted similar effects. These findings highlight the need to reconsider Gal-3 NT cleavage in formulating strategies to address tumor angiogenesis.