Vaccinia-Related Kinase 2 (VRK2) is an anti-apoptotic Ser/Thr kinase that enhances drug sensitivity in cancer cells. This protein exists in two isoforms: VRK2A, the longer variant, and VRK2B, which lacks the C-terminal region and transmembrane domain. While the therapeutic importance of VRK2 family proteins is known, the specific roles of VRK2A and its interplay with apoptotic regulator Bcl-xL (B-cell lymphoma-extra Large) remain elusive. Bcl-xL regulates cell death by interacting with BAX (B-cell lymphoma-2 Associated X-protein), controlling its cellular localization and influencing BAX-associated processes and signaling pathways. As VRK2A interacts with the Bcl-xL–BAX complex, comprehending its regulatory engagement with Bcl-xL presents potential avenues for intervening in diseases. Using a multi-disciplinary approach, this study provides information on the cellular localization of VRK2A and establishes its interaction with Bcl-xL in the cellular milieu, pinpointing the interacting site and elucidating its anti-apoptotic property within the complex. Furthermore, this study also put forth a model that highlights the importance of VRK2A in stabilizing the ternary complex, formed with Bcl-xL and BAX, thereby impeding BAX dissociation and hence apoptosis. Therefore, further investigations associated with this important revelation will provide cues for designing cancer therapeutics in the future.

中文翻译：

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阐明牛痘相关激酶 2A (VRK2A) C 末端结构域与特大 B 细胞淋巴瘤 (Bcl-xL) 的相互作用，以破译其在癌症中的抗凋亡作用

牛痘相关激酶 2 (VRK2) 是一种抗凋亡 Ser/Thr 激酶，可增强癌细胞的药物敏感性。该蛋白存在两种亚型：VRK2A（较长的变体）和 VRK2B（缺少 C 末端区域和跨膜结构域）。虽然 VRK2 家族蛋白的治疗重要性已为人所知，但 VRK2A 的具体作用及其与细胞凋亡调节因子 Bcl-xL（特大 B 细胞淋巴瘤）的相互作用仍然难以捉摸。Bcl-xL 通过与 BAX（B 细胞淋巴瘤 2 相关 X 蛋白）相互作用来调节细胞死亡，控制其细胞定位并影响 BAX 相关过程和信号通路。由于 VRK2A 与 Bcl-xL-BAX 复合物相互作用，了解其与 Bcl-xL 的调节作用为干预疾病提供了潜在途径。本研究采用多学科方法，提供了 VRK2A 细胞定位的信息，并建立了其与细胞环境中 Bcl-xL 的相互作用，查明相互作用位点并阐明了其在复合物内的抗凋亡特性。此外，这项研究还提出了一个模型，强调 VRK2A 在稳定 Bcl-xL 和 BAX 形成的三元复合物方面的重要性，从而阻止 BAX 解离，从而阻止细胞凋亡。因此，与这一重要发现相关的进一步研究将为未来设计癌症疗法提供线索。