Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Division of Electrical Engineering and Computer Science, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
Cell Death Dis. 2023 Apr 8;14(4):256. doi: 10.1038/s41419-023-05774-4.
Numerous studies have investigated the various cellular responses against genotoxic stress, including those mediated by focal adhesions. We here identified a novel type of focal adhesion remodelling that occurs under genotoxic stress conditions, which involves the replacement of active focal adhesion kinase (FAK) with FAK-related non-kinase (FRNK). FRNK stabilized focal adhesions, leading to strong cell-matrix adhesion, and FRNK-depleted cells were easily detached from extracellular matrix upon genotoxic stress. This remodelling occurred in a wide variety of cells. In vivo, the stomachs of Frnk-knockout mice were severely damaged by genotoxic stress, highlighting the protective role of FRNK against genotoxic stress. FRNK was also found to play a vital role in cancer progression, because FRNK depletion significantly inhibited cancer dissemination and progression in a mouse cancer model. Furthermore, in human cancers, FRNK was predominantly expressed in metastatic tissues and not in primary tissues. We hence conclude that this novel type of focal adhesion remodelling reinforces cell adhesion and acts against genotoxic stress, which results in the protection of normal tissues, but in turn facilitates cancer progression.
许多研究已经调查了针对遗传毒性应激的各种细胞反应，包括由粘着斑介导的反应。我们在这里发现了一种新的粘着斑重排类型，它发生在遗传毒性应激条件下，涉及活性粘着斑激酶（FAK）被 FAK 相关非激酶（FRNK）取代。FRNK 稳定粘着斑，导致与细胞外基质的强粘附，并且在遗传毒性应激下 FRNK 耗尽的细胞很容易从细胞外基质上脱落。这种重排发生在各种各样的细胞中。在体内，Frnk 基因敲除小鼠的胃受到遗传毒性应激的严重损伤，这突出了 FRNK 对遗传毒性应激的保护作用。FRNK 还被发现在癌症进展中起着至关重要的作用，因为 FRNK 耗竭显著抑制了小鼠癌症模型中的癌症扩散和进展。此外，在人类癌症中，FRNK 主要在转移性组织中表达，而不在原发性组织中表达。因此，我们得出结论，这种新型的粘着斑重排增强了细胞粘附并抵抗遗传毒性应激，从而保护了正常组织，但反过来又促进了癌症的进展。
