探討肌肉細胞中Dynamin-2進行胞吞作用的調控機制

Analysis of Dynamin-2 Regulatory Mechanism to Facilitates Endocytosis in Muscle cells

黎嘉雯(Jessica Laiman)

指導教授 ： 劉雅雯

國立臺灣大學/醫學院/分子醫學研究所/博士(2022年)

https://doi.org/10.6342/NTU202200410

摘要

骨骼肌是負責葡萄糖攝取與儲存的主要組織。在胰島素刺激下葡萄糖運輸蛋白，GLUT4，會從肌肉細胞内移至細胞膜上，而Dynamin-2 (Dyn2)會促進GLUT4的胞吞作用。Dyn2是一種參與在胞吞作用過程中促進細胞膜分裂的大型GTP水解酶。在肌肉細胞裡Dyn2是如何被調控目前尚不清楚。在本研究中，我們發現Bin1可透過SH3 domain 抑制Dyn2的活性。當Dyn2的Ser848被GSK3α磷酸化時或在Bin1的SH3區域被截斷的狀況下，Bin1對Dyn2的結合力下降因此降低了其對Dyn2的調控，Dyn2分裂膜的能力提升便增加了肌肉細胞中的胞吞作用。綜合以上結果，我們的研究證實Dyn2能藉由和Bin1以及 GSK3α之間的相互作用，在肌肉細胞的生理功能以及葡萄糖代謝扮演新穎的角色。

關鍵字

Bin1 ； Dyn2-PRD 磷酸化 ； GLUT4 ； GSK3 同功型 ； 胰島素信號傳導

並列摘要

Skeletal muscle is the predominant tissue for insulin-stimulated glucose uptake. Insulin promotes translocation of the glucose transporter, GLUT4, to muscle cell surface and Dynamin-2 (Dyn2) facilitates GLUT4 endocytosis upon insulin withdrawal. A gap remains in our understanding of how Dyn2 is regulated in muscle cells to mediates GLUT4 internalization. Here, we discover that the membrane fission activity of Dyn2 is inhibited in muscle cells through binding with the SH3 domain-containing protein Bin1. Phosphorylation of Serine848 on Dyn2 by GSK3 or SH3 domain truncations of Bin1, relieves Dyn2 from Bin1 inhibition. The augmented Dyn2 fission activity in muscle cells leads to GLUT4 internalization and Bin1-tubule vesiculation. Together, our findings reveal a new role for Dyn2 in regulating glucose homeostasis and muscle physiology via its interplay with Bin1 and GSK3α.

並列關鍵字

Bin1 ； Dyn2-PRD phosphorylation ； GLUT4 ； GSK3 isoforms ； Insulin signaling

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