Postdoctoral Innovation Practice Base, Postdoctoral Research Center of Jiangmen Central Hospital, Southern Medical University, Jiangmen 529030, China.
Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobank and Translational Research, Jiangmen Central Hospital, Jiangmen 529030, China.
Biosci Rep. 2023 Sep 27;43(9). doi: 10.1042/BSR20230057.
1,4,5-triphosphate 3-kinase A (ITPKA) was first described and characterized by Irvine et al. in 1986 and cloned by Takazawa et al. in 1990. It is one of the components of the Ca2+ and calmodulin signaling pathway and a substrate for cAMP-dependent kinase (PKA) and protein kinase C (PKC), and is mainly involved in the regulation of intracellular inositol polyphosphate signaling molecules. Through a series of studies, Sabine's team has found that ITPKA expression was up-regulated in a variety of cancer cells, and silencing ITPKA inhibited while overexpressing ITPKA promoted cancer cell migration in vitro and metastasis in vivo. The latest research from Sabine's team has demonstrated that in H1299 lung cancer cells, the mechanism by which ITPKA promoted migration and invasion was predominantly depending on the ability of binding to F-actin, which will induce cancer cells to form a tight flexible actin networks. Small molecule compounds targeting the IP3 kinase activity of ITPKA protein may only inhibit the migration and invasion of cancer cells caused by the enhanced ITPKA kinase activity under ATP stimulation, but not the cytoskeletal remodeling caused by the binding of ITPKA protein to F-actin and the driven migration and invasion of cancer cells. Therefore, targeted therapeutic strategy focusing on blocking the binding of ITPKA to F-actin is indispensable when designing the inhibitors targeting ITPKA protein.
三磷酸肌醇激酶 A（ITPKA）于 1986 年由 Irvine 等人首次描述和鉴定，并于 1990 年由 Takazawa 等人克隆。它是 Ca2+和钙调蛋白信号通路的组成部分之一，也是 cAMP 依赖性激酶（PKA）和蛋白激酶 C（PKC）的底物，主要参与细胞内肌醇多磷酸信号分子的调节。通过一系列研究，Sabine 团队发现 ITPKA 在多种癌细胞中表达上调，沉默 ITPKA 抑制，而过表达 ITPKA 促进体外癌细胞迁移和体内转移。Sabine 团队的最新研究表明，在 H1299 肺癌细胞中，ITPKA 促进迁移和侵袭的机制主要依赖于与 F- 肌动蛋白结合的能力，这将诱导癌细胞形成紧密的灵活肌动蛋白网络。针对 ITPKA 蛋白 IP3 激酶活性的小分子化合物可能仅抑制在 ATP 刺激下增强的 ITPKA 激酶活性引起的癌细胞迁移和侵袭，但不能抑制 ITPKA 蛋白与 F- 肌动蛋白结合引起的细胞骨架重塑以及癌细胞的驱动性迁移和侵袭。因此，在设计针对 ITPKA 蛋白的抑制剂时，针对 ITPKA 与 F- 肌动蛋白结合的靶向治疗策略是必不可少的。
