[论文解读] PEBP1/RKIP: from multiple functions to a common role in cellular processes

Françoise Schoentgen, Slavica Jonić|arXiv (Cornell University)|Feb 7, 2018

Melanoma and MAPK Pathways被引用 5

一句话总结

本综述提出，PEBP1/RKIP通过在膜和细胞骨架重排过程中调节分子相互作用，作为细胞信号转导的中心调节分子，其在癌症转移、神经退行性疾病、糖尿病及其他疾病中的多种功能可通过其抑制激酶活性和配体结合的共同机制加以解释。

ABSTRACT

PEBPs (PhosphatidylEthanolamine Binding Proteins) form a protein family widely present in the living world since they are encountered in microorganisms, plants and animals. In all organisms PEBPs appear to regulate important mechanisms that govern cell cycle, proliferation, differentiation and motility. In humans, three PEBPs have been identified, namely PEBP1, PEBP2 and PEBP4. PEBP1 and PEBP4 are the most studied as they are implicated in the development of various cancers. PEBP2 is specific of testes in mammals and was essentially studied in rats and mice where it is very abundant. A lot of information has been gained on PEBP1 also named RKIP (Raf Kinase Inhibitory protein) due to its role as a metastasis suppressor in cancer. PEBP1 was also demonstrated to be implicated in Alzheimers disease, diabetes and nephropathies. Furthermore, PEBP1 was described to be involved in many cellular processes, among them are signal transduction, inflammation, cell cycle, proliferation, adhesion, differentiation, apoptosis, autophagy, circadian rhythm and mitotic spindle checkpoint. On the molecular level, PEBP1 was shown to regulate several signaling pathways such as Raf/MEK/ERK, NFkB, PI3K/Akt/mTOR, p38, Notch and Wnt. PEBP1 acts by inhibiting most of the kinases of these signaling cascades. Moreover, PEBP1 is able to bind to a variety of small ligands such as ATP, phospholipids, nucleotides, flavonoids or drugs. Considering PEBP1 is a small cytoplasmic protein (21kDa), its involvement in so many diseases and cellular mechanisms is amazing. The aim of this review is to highlight the molecular systems that are common to all these cellular mechanisms in order to decipher the specific role of PEBP1. Recent discoveries enable us to propose that PEBP1 is a modulator of molecular interactions that control signal transduction during membrane and cytoskeleton reorganization.

研究动机与目标

• 识别PEBP1在多种疾病中发挥多样化细胞功能的共同分子机制。
• 解决一个单一的小蛋白（21 kDa）如何调控多条信号通路和多种疾病这一悖论。
• 统一理解PEBP1在信号转导、细胞凋亡和细胞骨架动力学中的作用。
• 提出PEBP1作为细胞重塑过程中分子相互作用调节者的中心功能角色。
• 将PEBP1与激酶、ATP、磷脂和药物相互作用的研究成果整合为一个连贯的调控模型。

提出的方法

• 系统性回顾人类、动物和微生物系统中关于PEBP1/RKIP的已发表文献。
• 分析PEBP1与关键信号激酶（如Raf、Akt、IKK）及其下游通路（Raf/MEK/ERK、NF-κB、PI3K/Akt/mTOR）的相互作用。
• 检查PEBP1的配体结合能力，包括ATP、磷脂、核苷酸、黄酮类化合物和药物。
• 对PEBP1与其他PEBPs（PEBP2、PEBP4）的结构和功能进行比较，突出其保守的调控机制。
• 整合PEBP1在疾病模型（癌症、阿尔茨海默病、糖尿病、肾病）中的数据，识别反复出现的分子主题。
• 提出PEBP1通过激酶抑制和配体感知调节膜和细胞骨架重排的模型。

实验结果

研究问题

• RQ1 是什么分子机制使PEBP1参与如此广泛的细胞过程和疾病？
• RQ2 PEBP1如何同时调控Raf/MEK/ERK、NF-κB和PI3K/Akt/mTOR等多条信号通路？
• RQ3 PEBP1能够结合ATP、磷脂和药物等多样配体的结构和功能基础是什么？
• RQ4 是否存在一个统一机制解释PEBP1在转移抑制、细胞凋亡、自噬和生物钟中的作用？
• RQ5 PEBP1作为激酶抑制剂的功能如何与它在细胞重塑过程中对细胞骨架和膜动力学的作用相关联？

主要发现

• PEBP1/RKIP通过与Raf-1激酶直接结合，抑制Raf/MEK/ERK通路，发挥转移抑制作用。
• PEBP1通过结合其上游激酶IKKβ，抑制NF-κB活化，从而抑制炎症反应。
• PEBP1通过与Akt相互作用，调节PI3K/Akt/mTOR通路，降低细胞存活和增殖信号。
• PEBP1可结合ATP、磷脂、核苷酸、黄酮类化合物和药物，表明其作为多功能分子传感器的作用。
• PEBP1在阿尔茨海默病中的作用与神经元中激酶信号失调有关，但确切机制仍在研究中。
• 尽管分子量较小（21 kDa），PEBP1仍通过在膜和细胞骨架重排过程中作为激酶活性和分子相互作用的中心调节者，协调多种细胞过程。