Rab40c regulates focal adhesions and PP6 activity by controlling ANKRD28 ubiquitylation.
Rab40c regulates focal adhesions and PP6 activity by controlling ANKRD28 ubiquitylation.
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DOI：
10.26508/lsa.202101346
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发表时间：
2022-09
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
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作者：
新型 Rab40c/CRL5 泛素化复合物在调节 PP6 活性和细胞迁移中的作用。 Rab40c 是一种包含 SOCS 盒的蛋白质，它与 Cullin5 结合形成泛素 E3 连接酶复合物 (Rab40c/CRL5) 以调节蛋白质泛素化。然而，Rab40c 的确切功能仍有待确定，并且哪些蛋白质是哺乳动物细胞中 Rab40c-Cullin5 介导的泛素化的靶标尚不清楚。在这里，我们表明，在迁移 MDA-MB-231 细胞中，Rab40c 调节粘着斑的数量、大小和分布。从机制上讲，我们发现 Rab40c 结合蛋白磷酸酶 6 (PP6) 复合物，并泛素化其亚基之一锚蛋白重复结构域 28 (ANKRD28)，从而导致其溶酶体降解。此外，我们发现 Rab40c 敲除细胞中 FAK 和 MOB1 的磷酸化降低，这可能有助于 Rab40c 的粘着斑位点调节。因此，我们提出了一个模型，其中 Rab40c/CRL5 调节 ANKRD28 泛素化和降解，导致 PP6 活性降低，最终影响 FAK 和 Hippo 通路信号传导，从而改变粘着斑动力学。
The role of novel Rab40c/CRL5 ubiquitylation complex in regulating PP6 activity and cell migration. Rab40c is a SOCS box–containing protein which binds Cullin5 to form a ubiquitin E3 ligase complex (Rab40c/CRL5) to regulate protein ubiquitylation. However, the exact functions of Rab40c remain to be determined, and what proteins are the targets of Rab40c-Cullin5–mediated ubiquitylation in mammalian cells are unknown. Here we showed that in migrating MDA-MB-231 cells Rab40c regulates focal adhesion’s number, size, and distribution. Mechanistically, we found that Rab40c binds the protein phosphatase 6 (PP6) complex and ubiquitylates one of its subunits, ankyrin repeat domain 28 (ANKRD28), thus leading to its lysosomal degradation. Furthermore, we identified that phosphorylation of FAK and MOB1 is decreased in Rab40c knock-out cells, which may contribute to focal adhesion site regulation by Rab40c. Thus, we propose a model where Rab40c/CRL5 regulates ANKRD28 ubiquitylation and degradation, leading to a decrease in PP6 activity, which ultimately affects FAK and Hippo pathway signaling to alter focal adhesion dynamics.
影响因子：
2.4
作者：
Yatsu A;Shimada H;Ohbayashi N;Fukuda M
通讯作者：
Fukuda M
DOI：
10.1007/978-1-0716-1346-7_11
发表时间：
2021
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Duncan ED;Lencer E;Linklater E;Prekeris R
通讯作者：
Prekeris R