Exclusion of NUMB Exon12 Controls Cancer Cell Migration through Regulation of Notch1-SMAD3 Crosstalk.
Exclusion of NUMB Exon12 Controls Cancer Cell Migration through Regulation of Notch1-SMAD3 Crosstalk.
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排除 NUMB Exon12 通过调节 Notch1-SMAD3 串扰控制癌细胞迁移
DOI：
10.3390/ijms23084363
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发表时间：
2022-04-14
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
NUMB是一种内吞衔接蛋白，由于选择性剪接调节而含有四种亚型（p65、p66、p71和p72）。在这里，我们发现NUMB外显子12（E12）跳跃亚型p65/p66促进上皮间质转化（EMT）和癌细胞迁移在体外，并促进小鼠的癌症转移，而E12包括p71/p72亚型减弱这些影响。从机制上讲，p65/p66同种型显著增加Notch 1通过早期内体（EE）的分选，以增强Notch 1活性。相反，p71/p72亚型通过泛素化Notch 1胞内结构域（N1 ICD）并促进其降解而充当Notch 1的负调节剂。此外，我们观察到N1 ICD和SMAD 3之间的相互作用对于它们自身的稳定以及对于NUMB介导的EMT反应和细胞迁移是重要的。N1 ICD或SMAD 3过表达可以显著地消除p65/p66敲低中所见的迁移减少，并且Notch 1或SMAD 3敲低挽救了p66过表达中所见的迁移优势。综上所述，我们的研究提供了NUMB亚型对Notch 1-SMAD 3串扰的相反调节机制的见解，并将其鉴定为EMT和癌细胞迁移的关键调节因子。
NUMB is an endocytic adaptor protein that contains four isoforms (p65, p66, p71 and p72) due to alternative splicing regulation. Here, we show that NUMB exon12 (E12)-skipping isoforms p65/p66 promote epithelial to mesenchymal transition (EMT) and cancer cell migration in vitro, and facilitate cancer metastasis in mice, whereas E12-included p71/p72 isoforms attenuate these effects. Mechanistically, p65/p66 isoforms significantly increase the sorting of Notch1 through early endosomes (EEs) for enhanced Notch1 activity. In contrast, p71/p72 isoforms act as negative regulators of Notch1 by ubiquitylating the Notch1 intracellular domain (N1ICD) and promoting its degradation. Moreover, we observed that the interaction between N1ICD and SMAD3 is important for their own stabilization, and for NUMB-mediated EMT response and cell migration. Either N1ICD or SMAD3 overexpression could significantly recuse the migration reduction seen in the p65/p66 knockdown, and Notch1 or SMAD3 knockdown rescued the migration advantage seen in the overexpression of p66. Taken all together, our study provides mechanistic insights into the opposite regulation of Notch1-SMAD3 crosstalk by NUMB isoforms and identifies them as critical regulators of EMT and cancer cell migration.
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影响因子：
39.3
作者：
Liu S;Ren J;Ten Dijke P
通讯作者：
Ten Dijke P
影响因子：
64.8
作者：
Colaluca, Ivan N.;Tosoni, Daniela;Di Fiore, Pier Paolo
通讯作者：
Di Fiore, Pier Paolo
影响因子：
16.6
作者：
Natsuizaka M;Whelan KA;Kagawa S;Tanaka K;Giroux V;Chandramouleeswaran PM;Long A;Sahu V;Darling DS;Que J;Yang Y;Katz JP;Wileyto EP;Basu D;Kita Y;Natsugoe S;Naganuma S;Klein-Szanto AJ;Diehl JA;Bass AJ;Wong KK;Rustgi AK;Nakagawa H
通讯作者：
Nakagawa H
DOI：
10.1073/pnas.96.18.10472
发表时间：
1999-08-31
影响因子：
11.1
作者：
Verdi, JM;Bashirullah, A;Lipshitz, HD
通讯作者：
Lipshitz, HD
影响因子：
10.5
作者：
Timmerman, LA;Grego-Bessa, J;de la Pompa, JL
通讯作者：
de la Pompa, JL