Serine/Threonine Kinase 3-Phosphoinositide-Dependent Protein Kinase-1 (PDK1) as a Key Regulator of Cell Migration and Cancer Dissemination.
Serine/Threonine Kinase 3-Phosphoinositide-Dependent Protein Kinase-1 (PDK1) as a Key Regulator of Cell Migration and Cancer Dissemination.
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丝氨酸/苏氨酸激酶3-磷酸肌醇依赖性蛋白激酶1（PDK 1）作为细胞迁移和癌症扩散的关键调节因子。
DOI：
10.3390/cancers9030025
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发表时间：
2017-03-11
期刊：
影响因子：
5.2
通讯作者：
Primo L
中科院分区：
文献类型：
--
作者：
Di Blasio L;Gagliardi PA;Puliafito A;Primo L
剖析支配真核细胞运动的细胞信号传导是现代细胞生物学的基本任务之一，不仅因为细胞迁移在其中至关重要的大量生理过程，而且更因为病理过程，特别是肿瘤侵袭和转移。细胞迁移需要至少四个主要过程的协调：细胞内信号的极化、肌动蛋白细胞骨架和膜延伸的调节、粘着斑和整合素信号以及收缩力的产生和后部收缩。在参与运动调节的分子组分中，磷脂酰肌醇-3-激酶（PI 3 K）途径已被证明发挥重要作用。这种途径的关键节点由丝氨酸/苏氨酸激酶3-磷酸肌醇依赖性蛋白激酶-1（PDPK 1或PDK 1）代表。PDK 1及其大多数底物属于AGC激酶家族（与cAMP依赖性蛋白激酶1、环鸟苷一磷酸依赖性蛋白激酶和蛋白激酶C相关），并控制PI 3 K或其他途径（如RAS GTP酶-MAPK（促分裂原活化蛋白激酶））下游的大量细胞过程。有趣的是，已经证明PDK 1通过激活几种蛋白质，如蛋白激酶B/Akt（PKB/Akt）、强直性肌营养不良相关的CDC 42结合激酶α（MRCKα）、Rho相关的含有卷曲螺旋的蛋白激酶1（ROCK 1）、磷脂酶C γ 1（PLCγ1）和β3整联蛋白，对细胞迁移的每个步骤的调节至关重要。此外，PDK 1还调节癌细胞侵袭，因此代表了预防人类患者癌症转移的可能靶点。本文综述了PDK 1控制细胞迁移过程的各种机制，包括细胞极化、肌动蛋白细胞骨架和粘着斑调节，并讨论了PDK 1在癌细胞侵袭和扩散中的作用。
Dissecting the cellular signaling that governs the motility of eukaryotic cells is one of the fundamental tasks of modern cell biology, not only because of the large number of physiological processes in which cell migration is crucial, but even more so because of the pathological ones, in particular tumor invasion and metastasis. Cell migration requires the coordination of at least four major processes: polarization of intracellular signaling, regulation of the actin cytoskeleton and membrane extension, focal adhesion and integrin signaling and contractile forces generation and rear retraction. Among the molecular components involved in the regulation of locomotion, the phosphatidylinositol-3-kinase (PI3K) pathway has been shown to exert fundamental role. A pivotal node of such pathway is represented by the serine/threonine kinase 3-phosphoinositide-dependent protein kinase-1 (PDPK1 or PDK1). PDK1, and the majority of its substrates, belong to the AGC family of kinases (related to cAMP-dependent protein kinase 1, cyclic Guanosine monophosphate-dependent protein kinase and protein kinase C), and control a plethora of cellular processes, downstream either to PI3K or to other pathways, such as RAS GTPase-MAPK (mitogen-activated protein kinase). Interestingly, PDK1 has been demonstrated to be crucial for the regulation of each step of cell migration, by activating several proteins such as protein kinase B/Akt (PKB/Akt), myotonic dystrophy-related CDC42-binding kinases alpha (MRCKα), Rho associated coiled-coil containing protein kinase 1 (ROCK1), phospholipase C gamma 1 (PLCγ1) and β3 integrin. Moreover, PDK1 regulates cancer cell invasion as well, thus representing a possible target to prevent cancer metastasis in human patients. The aim of this review is to summarize the various mechanisms by which PDK1 controls the cell migration process, from cell polarization to actin cytoskeleton and focal adhesion regulation, and finally, to discuss the evidence supporting a role for PDK1 in cancer cell invasion and dissemination.