Department of Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Amarillo, TX 79106, USA.
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, USA.
Neoplasia. 2022 Oct;32:100819. doi: 10.1016/j.neo.2022.100819. Epub 2022 Jul 12.
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.
Abi 蛋白家族是 WAVE 调节复合物 (WRC) 的一个组成部分，也是 Abelson (Abl) 酪氨酸激酶的下游靶标。事实上，Abi 蛋白还与多种膜蛋白和细胞内信号分子相互作用，使这些蛋白处于控制细胞骨架功能和癌细胞转移的网络的中心位置。在这里，我们鉴定出 Abi 蛋白中的一个基序，该基序符合结合 Cbl-酪氨酸激酶结合域的受体和非受体酪氨酸激酶的共有序列。该基序中酪氨酸 213 的磷酸化对于 Abi 的降解至关重要。Bcr-Abl 转化的白血病细胞中 c-Cbl 和 Cbl B 的双重敲除会导致 Abi1、Abi2 和 WAVE2 的降解。此外，Abi1 的敲除会减少 Bcr-Abl 阳性白血病细胞中Src 家族激酶 Lyn 的激活，并促进乳腺癌细胞中 EGF 诱导的 EGF 受体下调。重要的是，Abi1 的耗竭会阻碍乳腺癌细胞在体外的侵袭和在小鼠异种移植中的转移。总之，这些研究揭示了 WRC 和受体/非受体酪氨酸激酶被调控的新机制，并将 Abi1 鉴定为转移性乳腺癌的潜在治疗靶点。
