Studies on integrinα3β1-mediated signaling

整合素α3β1介导的信号传导研究

• 批准号: 14580697
• 负责人: GU Jianguo
• 金额: $ 2.3万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580697/
• 关键词: basement membrane; integrin; laminin; phosphotyrosine; matrix metallonroteinase; signal; N-glycan; 糖鎖

The α3β1 integrin-mediated signaling events triggered by cell adhesion to laminin-10/11(LN-10/11) are quite different from those triggered by adhesion to fibronectin (FN). LN-10/11 preferentially activates Rac, but not Rho, through an α3β1 integrin-dependent pathway involving a p130Cas-CrkII-DOCK18O complex, thereby strongly promoting cell migration through enhanced formation of lamellipodia. On the other hand, the intracellular signaling pathways regulating cell survival focusing on two distinct signaling pathways involving PI 3-kinase/Akt and MEKi/ERK have been investigated. LN-10/11 is more potent than FN in suppressing apoptosis induced by serum deprivations The anti-apoptotic effects of LN-10I11 could be inhibited by the PI 3-kinase inhibitor wortmannin, whereas the anti-apoptotic effects of FN were inhibited by the MEKi inhibitor PD98059. Our results provide clear evidence that different signaling pathways leading to cell survival are activated, on different ECM ligands. Furthermore, remodeling of N-glycans of the integrin could also modulate its ligand binding and integrin-mediated signaling. Since laminins are the major components of the basement membrane of epithelium, our work supports the notion that a function of the basement membrane is to provide distinctive cell survival signals for establishment and maintenance of epithelial tissue.

细胞粘附层粘连蛋白-10/11 (LN-10/11) 触发的 α3β1 整合素介导的信号事件与粘附纤连蛋白 (FN) 触发的信号事件有很大不同，它优先激活 Rac，但不激活 Rho。 ，通过涉及 p130Cas-CrkII-DOCK18O 复合物的 α3β1 整合素依赖性途径，从而促进细胞迁移另一方面，已研究了调节细胞存活的细胞内信号传导途径，其中涉及两种不同的信号传导途径 PI 3-激酶/Akt 和 MEKi/ERK，其作用比 FN 更有效。抑制血清剥夺诱导的细胞凋亡 LN-10I11 的抗细胞凋亡作用可以被 PI 3 激酶抑制剂渥曼青霉素抑制，而FN 的抗凋亡作用受到 MEKi 抑制剂 PD98059 的抑制，我们的结果提供了明确的证据，表明导致细胞存活的不同信号通路在不同的 ECM 配体上被激活。此外，整合素 N-聚糖的重塑也可以调节其配体。由于层粘连蛋白是上皮基底膜的主要成分，因此我们的工作支持这样的观点：基底膜的功能是提供独特的细胞存活。上皮组织建立和维持的信号。

项目成果

Isaji, T., gu, J., Nishiuchi, R., Zhao, Y, Takahashi, M., Miyoshi, E., Honke, K., Sekiguchi, K., Taniguchi, N.: "Introduction of bisecting GlcNAc into integrin α5β1 reduces ligand binding and down-regulates cell adhesion and cell migration."J.Biol.Chem. 2

Isaji, T.、gu, J.、Nishiuchi, R.、Zhao, Y、Takahashi, M.、Miyoshi, E.、Honke, K.、Sekiguchi, K.、Taniguchi, N.：“将 GlcNAc 等分引入整合素 α5β1 减少配体结合并下调细胞粘附和细胞迁移。”J.Biol.Chem. 2

Gu, J., et al.: "Laminin-10/11 and Fibronectin Differentially Regulate Integrin-dependent Rho and Rac Activition via p130^<Cas>/Crkll/DOCK180 Pathway"J. Biol. Chem.. 276・29. 27090-27097 (2001)

Gu, J., et al.：“Laminin-10/11 和 Fibronectin 通过 p130^<Cas>/Crkll/DOCK180 通路差异调节整合素依赖性 Rho 和 Rac 激活”J Biol. 276・29。 -27097 (2001)

Kozaki, T., Matsui, Y, Gu., J., Nishiuchi, R., Sugiura, N., Kimata, K., Ozono, K., Yoshikawa, H.Sekiguchi, K.: "Recombinant Expression and Characterization of a Novel Fibronectin Isoform Expressed in Cartilaginous Tissues."J.Biol.Chem. 278. 50546-50553 (2

Kozaki, T.、Matsui, Y, Gu., J.、Nishiuchi, R.、Sugiura, N.、Kimata, K.、Ozono, K.、Yoshikawa, H.Sekiguchi, K.：“重组表达和表征

Shigeta, M., et al.: "CD151 regulates epithelial cell-cell adhesion through PKC- and Cdc42-dependent actin cytoskeletal reorganization."J.Cell Biol.. 163. 165-176 (2003)

Shigeta, M., 等人：“CD151 通过 PKC 和 Cdc42 依赖性肌动蛋白细胞骨架重组调节上皮细胞间粘附。”J.Cell Biol.. 163. 165-176 (2003)

Gu, J., et al.: "Matrix metalloproteinase-2 is involved in A549 cell migration on laminin-10/11"Biochem. Biophys. Res. Commun.. 296・1. 69-73 (2002)

Gu, J., et al.：“基质金属蛋白酶-2 参与层粘连蛋白-10/11 上的 A549 细胞迁移”Biochem. Commun. 296·1 (2002)。