Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5B 2K3, Canada.
Cells. 2023 Feb 7;12(4):534. doi: 10.3390/cells12040534.
Cytoskeleton organization and dynamics are rapidly regulated by post-translational modifications of key target proteins. Acting downstream of the Cdc42 GTPase, the myotonic dystrophy-related Cdc42-binding kinases MRCKα, MRCKβ, and MRCKγ have recently emerged as important players in cytoskeleton regulation through the phosphorylation of proteins such as the regulatory myosin light chain proteins. Compared with the closely related Rho-associated coiled-coil kinases 1 and 2 (ROCK1 and ROCK2), the contributions of the MRCK kinases are less well characterized, one reason for this being that the discovery of potent and selective MRCK pharmacological inhibitors occurred many years after the discovery of ROCK inhibitors. The disclosure of inhibitors, such as BDP5290 and BDP9066, that have marked selectivity for MRCK over ROCK, as well as the dual ROCK + MRCK inhibitor DJ4, has expanded the repertoire of chemical biology tools to study MRCK function in normal and pathological conditions. Recent research has used these novel inhibitors to establish the role of MRCK signalling in epithelial polarization, phagocytosis, cytoskeleton organization, cell motility, and cancer cell invasiveness. Furthermore, pharmacological MRCK inhibition has been shown to elicit therapeutically beneficial effects in cell-based and in vivo studies of glioma, skin, and ovarian cancers.
细胞骨架的组织和动态通过关键靶蛋白的翻译后修饰迅速调节。肌强直性营养不良相关的 Cdc42 结合激酶 MRCKα、MRCKβ 和 MRCKγ 作为 Cdc42 GTP 酶的下游效应物，通过磷酸化肌球蛋白轻链等蛋白，新近成为细胞骨架调节的重要参与者。与密切相关的 Rho 相关卷曲螺旋激酶 1 和 2（ROCK1 和 ROCK2）相比，MRCK 激酶的作用尚未得到很好的描述，其中一个原因是，MRCK 药理学抑制剂的发现比 ROCK 抑制剂晚了很多年。BDP5290 和 BDP9066 等对 MRCK 具有明显选择性的抑制剂的发现，以及双重 ROCK + MRCK 抑制剂 DJ4 的发现，扩展了化学生物学工具的应用范围，可用于研究正常和病理条件下的 MRCK 功能。最近的研究利用这些新型抑制剂确定了 MRCK 信号在上皮极化、吞噬作用、细胞骨架组织、细胞迁移和癌细胞侵袭中的作用。此外，在神经胶质瘤、皮肤和卵巢癌的基于细胞和体内研究中，MRCK 的药理学抑制已显示出治疗有益的效果。
