Department of Health Sciences, School of Arts and Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
Albert Einstein College of Medicine, Bronx, NY, USA.
Cell Microbiol. 2015 Nov;17(11):1670-82. doi: 10.1111/cmi.12464. Epub 2015 Jun 19.
CagA is a multifunctional toxin of Helicobacter pylori that is secreted into host epithelial cells by a type IV secretion system. Following host cell translocation, CagA interferes with various host-cell signalling pathways. Most notably this toxin is involved in the disruption of apical-basolateral cell polarity and cell adhesion, as well as in the induction of cell proliferation, migration and cell morphological changes. These are processes that also play an important role in epithelial-to-mesenchymal transition and cancer cell invasion. In fact, CagA is considered as the only known bacterial oncoprotein. The cellular effects are triggered by a variety of CagA activities including the inhibition of serine-threonine kinase Par1b/MARK2 and the activation of tyrosine phosphatase SHP-2. Additionally, CagA was described to affect the activity of Src family kinases and C-terminal Src kinase (Csk) suggesting that interference with multiple cellular kinase- and phosphatase-associated signalling pathways is a major function of CagA. Here, we describe the effect of CagA on protein kinase C-related kinase 2 (PRK2), which acts downstream of Rho GTPases and is known to affect cytoskeletal rearrangements and cell polarity. CagA interacts with PRK2 and inhibits its kinase activity. Because PRK2 has been linked to cytoskeletal rearrangements and establishment of cell polarity, we suggest that CagA may hijack PRK2 to further manipulate cancer-related signalling pathways.
CagA 是幽门螺杆菌的一种多功能毒素，通过 IV 型分泌系统被分泌到宿主上皮细胞中。在宿主细胞易位后，CagA 干扰各种宿主细胞信号通路。特别是，这种毒素参与破坏顶端-基底外侧细胞极性和细胞黏附，以及诱导细胞增殖、迁移和细胞形态变化。这些过程在上皮-间充质转化和癌细胞侵袭中也起着重要作用。事实上，CagA 被认为是唯一已知的细菌癌蛋白。细胞效应是由 CagA 的多种活性触发的，包括抑制丝氨酸-苏氨酸激酶 Par1b/MARK2 和激活酪氨酸磷酸酶 SHP-2。此外，CagA 被描述为影响Src 家族激酶和 C 端Src 激酶（Csk）的活性，这表明干扰多种细胞激酶和磷酸酶相关信号通路是 CagA 的主要功能。在这里，我们描述了 CagA 对蛋白激酶 C 相关激酶 2（PRK2）的影响，PRK2 作为 Rho GTPases 的下游分子，已知会影响细胞骨架重排和细胞极性。CagA 与 PRK2 相互作用并抑制其激酶活性。由于 PRK2 与细胞骨架重排和细胞极性的建立有关，我们认为 CagA 可能劫持 PRK2 来进一步操纵与癌症相关的信号通路。
