The Abl/Abi signaling links WAVE regulatory complex to Cbl E3 ubiquitin ligase and is essential for breast cancer cell metastasis.
The Abl/Abi signaling links WAVE regulatory complex to Cbl E3 ubiquitin ligase and is essential for breast cancer cell metastasis.
复制标题
DOI：
10.1016/j.neo.2022.100819
复制
发表时间：
2022-10
期刊：
影响因子：
4.8
通讯作者：
Dai, Zonghan
中科院分区：
文献类型：
--
作者：
Jiang, Peixin;Tang, Suni;Hudgins, Hogan;Smalligan, Tate;Zhou, Xue;Kamat, Anuja;Dharmarpandi, Janaki;Naguib, Tarek;Liu, Xinli;Dai, Zonghan
关键词：
Cbl-TKB结合基序调节阿比特龙和WAVE调节复合物的稳定性。Abl激酶充当激活Cbl介导的Abi/WRC降解的开关。Abi 1的消耗损害EGFR和Src家族激酶信号传导。Abi 1是乳腺癌细胞侵袭和肺转移所必需的。Abelson相互作用蛋白（Abel son interactor，Abi）家族是WAVE调节复合物（regulatory complex，WRC）的组成部分，是Abel son酪氨酸激酶的下游靶点。Abi蛋白还与不同的膜蛋白和细胞内信号分子相互作用的事实将这些蛋白质置于控制细胞骨架功能和癌细胞转移的网络中的中心位置。在这里，我们鉴定了Abi蛋白中的基序，该基序符合在一组受体和非受体酪氨酸激酶中发现的与Cbl-酪氨酸激酶结合结构域结合的共有序列。该基序中酪氨酸213的磷酸化是阿比特龙降解所必需的。在Bcr-Abl转化的白血病细胞中c-Cbl和Cbl B的双重敲除消除Abi 1、Abi 2和WAVE 2降解。此外，Abi 1的敲除降低了Bcr-Abl阳性白血病细胞中Src家族激酶林恩的激活，并促进了乳腺癌细胞中EGF诱导的EGF受体下调。重要的是，Abi 1缺失阻碍了乳腺癌细胞的体外侵袭和小鼠异种移植物中的转移。总之，这些研究揭示了WRC和受体/非受体酪氨酸激酶调节的新机制，并将Abi 1确定为转移性乳腺癌的潜在治疗靶点。
A Cbl-TKB binding motif regulates the stability of Abi and WAVE regulatory complex. Abl kinases serve as a switch to activate Cbl-mediated Abi/WRC degradation. Depletion of Abi1 impairs EGFR and Src family kinases signaling. Abi1 is essential for breast cancer cell invasion and lung metastasis. The family of Abelson interactor (Abi) proteins is a component of WAVE regulatory complex (WRC) and a downstream target of Abelson (Abl) tyrosine kinase. The fact that Abi proteins also interact with diverse membrane proteins and intracellular signaling molecules places these proteins at a central position in the network that controls cytoskeletal functions and cancer cell metastasis. Here, we identified a motif in Abi proteins that conforms to consensus sequences found in a cohort of receptor and non-receptor tyrosine kinases that bind to Cbl-tyrosine kinase binding domain. The phosphorylation of tyrosine 213 in this motif is essential for Abi degradation. Double knockout of c-Cbl and Cbl B in Bcr-Abl-transformed leukemic cells abolishes Abi1, Abi2, and WAVE2 degradation. Moreover, knockout of Abi1 reduces Src family kinase Lyn activation in Bcr-Abl-positive leukemic cells and promotes EGF-induced EGF receptor downregulation in breast cancer cells. Importantly, Abi1 depletion impeded breast cancer cell invasion in vitro and metastasis in mouse xenografts. Together, these studies uncover a novel mechanism by which the WRC and receptor/non-receptor tyrosine kinases are regulated and identify Abi1 as a potential therapeutic target for metastatic breast cancer.
登录
查看更多内容
肌动蛋白调节波复合物的结构和控制。
影响因子：
64.8
作者：
Chen, Zhucheng;Borek, Dominika;Padrick, Shae B.;Gomez, Timothy S.;Metlagel, Zoltan;Ismail, Ayman M.;Umetani, Junko;Billadeau, Daniel D.;Otwinowski, Zbyszek;Rosen, Michael K.
通讯作者：
Rosen, Michael K.
影响因子：
8
作者：
Kim, M;Tezuka, T;Yamamoto, T
通讯作者：
Yamamoto, T
DOI：
10.1083/jcb.200206079
发表时间：
2003-01-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Innocenti M;Frittoli E;Ponzanelli I;Falck JR;Brachmann SM;Di Fiore PP;Scita G
通讯作者：
Scita G
DOI：
10.1016/j.bbamcr.2012.10.010
发表时间：
2013-01
影响因子：
5.1
作者：
Mohapatra, Bhopal;Ahmad, Gulzar;Nadeau, Scott;Zutshi, Neha;An, Wei;Scheffe, Sarah;Dong, Lin;Feng, Dan;Goetz, Benjamin;Arya, Priyanka;Bailey, Tameka A.;Palermo, Nicholas;Borgstahl, Gloria E. O.;Natarajan, Amarnath;Raja, Srikumar M.;Naramura, Mayumi;Band, Vimla;Band, Hamid
通讯作者：
Band, Hamid
影响因子：
15.3
作者：
Park, Heon;Staehling-Hampton, Karen;Iritani, Brian M.
通讯作者：
Iritani, Brian M.