Huang Qingwen, Zhang Rui, Xia Yun, Shen Jie, Dong Hongliang, Li Xiaolan, Tao Deding, Xie Daxing, Liu Liang
Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
Department of GI Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
iScience. 2023 Aug 11;26(9):107606. doi: 10.1016/j.isci.2023.107606. eCollection 2023 Sep 15.
Invadopodia, being actin-rich membrane protrusions, play a vital role in tumor cell invasion and metastasis. Our previous studies have revealed some functions of the DOC-2/DAB2 interacting protein (DAB2IP) as a tumor suppressor. Nevertheless, the specific role and mechanism of DAB2IP in invadopodia formation remain unclear. Here, we find that DAB2IP effectively suppresses invadopodia formation and metastasis in breast cancer, both and . Additionally, DAB2IP could downregulate anaplastic lymphoma kinase (ALK), resulting in the inhibition of tyrosine phosphorylation of Cortactin and the prevention of invadopodia formation. DAB2IP competitively antagonizes the interaction between the deubiquitinating enzyme Ubiquitin-specific peptidase 10 (USP10) and ALK, leading to a decrease in the abundance of ALK protein. In summary, DAB2IP impairs the stability of ALK through USP10-dependent deubiquitination, suppressing Cortactin phosphorylation, thereby inhibiting invadopodia formation and metastasis of breast cancer cells. Furthermore, this study suggests a potential therapeutic strategy for breast cancer treatment.
侵袭伪足是富含肌动蛋白的膜突出物，在肿瘤细胞侵袭和转移中起重要作用。我们之前的研究揭示了DOC-2/DAB2相互作用蛋白（DAB2IP）作为一种肿瘤抑制因子的一些功能。然而，DAB2IP在侵袭伪足形成中的具体作用和机制仍不清楚。在此，我们发现DAB2IP能有效抑制乳腺癌中侵袭伪足的形成和转移。此外，DAB2IP可下调间变性淋巴瘤激酶（ALK），导致皮层肌动蛋白酪氨酸磷酸化受到抑制，并防止侵袭伪足的形成。DAB2IP竞争性拮抗去泛素化酶泛素特异性肽酶10（USP10）与ALK之间的相互作用，导致ALK蛋白丰度降低。总之，DAB2IP通过USP10依赖的去泛素化作用损害ALK的稳定性，抑制皮层肌动蛋白磷酸化，从而抑制乳腺癌细胞侵袭伪足的形成和转移。此外，本研究为乳腺癌治疗提出了一种潜在的治疗策略。
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