Department of Pharmacology, Columbia University, New York, NY 10032, USA.
Mol Pharmacol. 2012 Mar;81(3):284-91. doi: 10.1124/mol.111.075986. Epub 2011 Dec 21.
Protein kinase D1 (PKD1) is a stress-activated serine/threonine kinase that plays a vital role in various physiologically important biological processes, including cell growth, apoptosis, adhesion, motility, and angiogenesis. Dysregulated PKD1 expression also contributes to the pathogenesis of certain cancers and cardiovascular disorders. Studies to date have focused primarily on the canonical membrane-delimited pathway for PKD1 activation by G protein-coupled receptors or peptide growth factors. Here, agonist-dependent increases in diacylglycerol accumulation lead to the activation of protein kinase C (PKC) and PKC-dependent phosphorylation of PKD1 at two highly conserved serine residues in the activation loop; this modification increases PKD1 catalytic activity, as assessed by PKD1 autophosphorylation at a consensus phosphorylation motif at the extreme C terminus. However, recent studies expose additional controls and consequences for PKD1 activation loop and C-terminal phosphorylation as well as additional autophosphorylation reactions and trans-phosphorylations (by PKC and other cellular enzymes) that contribute to the spatiotemporal control of PKD1 signaling in cells. This review focuses on the multisite phosphorylations that are known or predicted to influence PKD1 catalytic activity and may also influence docking interactions with cellular scaffolds and trafficking to signaling microdomains in various subcellular compartments. These modifications represent novel targets for the development of PKD1-directed pharmaceuticals for the treatment of cancers and cardiovascular disorders.
蛋白激酶 D1(PKD1)是一种应激激活的丝氨酸/苏氨酸激酶,在多种生理重要的生物学过程中发挥着至关重要的作用,包括细胞生长、凋亡、黏附、迁移和血管生成。PKD1 表达失调也导致某些癌症和心血管疾病的发病机制。迄今为止的研究主要集中在 PKD1 通过 G 蛋白偶联受体或肽生长因子的经典膜限制定激活途径。在这里,激动剂依赖性二酰基甘油积累的增加导致蛋白激酶 C(PKC)的激活和 PKC 依赖性 PKD1 在激活环中两个高度保守的丝氨酸残基的磷酸化;这种修饰增加了 PKD1 的催化活性,如通过 PKD1 在极端 C 末端的共识磷酸化模体的自身磷酸化来评估。然而,最近的研究揭示了 PKD1 激活环和 C 末端磷酸化的额外控制和后果,以及其他自身磷酸化反应和转磷酸化(由 PKC 和其他细胞酶),这些反应有助于 PKD1 在细胞中的时空信号转导控制。本综述重点介绍了已知或预测影响 PKD1 催化活性的多部位磷酸化,这些磷酸化也可能影响与细胞支架的对接相互作用和向各种亚细胞隔室中的信号转导微区的运输。这些修饰代表了针对癌症和心血管疾病的 PKD1 靶向药物开发的新型靶标。