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周期素依赖性激酶 5 介导多效蛋白诱导的内皮细胞迁移。

Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration.

机构信息

Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, GR26504, Patras, Greece.

Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA.

出版信息

Sci Rep. 2018 Apr 12;8(1):5893. doi: 10.1038/s41598-018-24326-x.

DOI:10.1038/s41598-018-24326-x
PMID:29651006
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5897396/
Abstract

Pleiotrophin (PTN) stimulates endothelial cell migration through binding to receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and αβ integrin. Screening for proteins that interact with RPTPβ/ζ and potentially regulate PTN signaling, through mass spectrometry analysis, identified cyclin-dependent kinase 5 (CDK5) activator p35 among the proteins displaying high sequence coverage. Interaction of p35 with the serine/threonine kinase CDK5 leads to CDK5 activation, known to be implicated in cell migration. Protein immunoprecipitation and proximity ligation assays verified p35-RPTPβ/ζ interaction and revealed the molecular association of CDK5 and RPTPβ/ζ. In endothelial cells, PTN activates CDK5 in an RPTPβ/ζ- and phosphoinositide 3-kinase (PI3K)-dependent manner. On the other hand, c-Src, αβ and ERK1/2 do not mediate the PTN-induced CDK5 activation. Pharmacological and genetic inhibition of CDK5 abolished PTN-induced endothelial cell migration, suggesting that CDK5 mediates PTN stimulatory effect. A new pyrrolo[2,3-α]carbazole derivative previously identified as a CDK1 inhibitor, was found to suppress CDK5 activity and eliminate PTN stimulatory effect on cell migration, warranting its further evaluation as a new CDK5 inhibitor. Collectively, our data reveal that CDK5 is activated by PTN, in an RPTPβ/ζ-dependent manner, regulates PTN-induced cell migration and is an attractive target for the inhibition of PTN pro-angiogenic properties.

摘要

多效蛋白（PTN）通过与受体蛋白酪氨酸磷酸酶β/ζ（RPTPβ/ζ）和αβ 整合素结合来刺激内皮细胞迁移。通过质谱分析筛选与 RPTPβ/ζ 相互作用并可能调节 PTN 信号的蛋白质，在显示高序列覆盖率的蛋白质中鉴定出细胞周期蛋白依赖性激酶 5（CDK5）激活剂 p35。p35 与丝氨酸/苏氨酸激酶 CDK5 的相互作用导致 CDK5 的激活，已知与细胞迁移有关。蛋白质免疫沉淀和邻近连接测定验证了 p35-RPTPβ/ζ 的相互作用，并揭示了 CDK5 和 RPTPβ/ζ 的分子关联。在内皮细胞中，PTN 通过 RPTPβ/ζ 和磷酸肌醇 3-激酶（PI3K）依赖性方式激活 CDK5。另一方面，c-Src、αβ 和 ERK1/2 不介导 PTN 诱导的 CDK5 激活。CDK5 的药理学和遗传抑制消除了 PTN 诱导的内皮细胞迁移，表明 CDK5 介导了 PTN 的刺激作用。先前被鉴定为 CDK1 抑制剂的一种新型吡咯并[2,3-α]咔唑衍生物，被发现抑制 CDK5 活性并消除 PTN 对细胞迁移的刺激作用，这使其进一步作为新型 CDK5 抑制剂进行评估。总之，我们的数据表明 CDK5 通过 PTN 以 RPTPβ/ζ 依赖的方式被激活，调节 PTN 诱导的细胞迁移，是抑制 PTN 促血管生成特性的有吸引力的靶标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/0ce4fab34b0e/41598_2018_24326_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/68d53ec51fd9/41598_2018_24326_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/0aa52428af86/41598_2018_24326_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/671c1217cfc8/41598_2018_24326_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/b070cce6f421/41598_2018_24326_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/a48dff0d21d6/41598_2018_24326_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/ff70716ad017/41598_2018_24326_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/0ce4fab34b0e/41598_2018_24326_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/68d53ec51fd9/41598_2018_24326_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/0aa52428af86/41598_2018_24326_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/671c1217cfc8/41598_2018_24326_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/b070cce6f421/41598_2018_24326_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/a48dff0d21d6/41598_2018_24326_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/ff70716ad017/41598_2018_24326_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c187/5897396/0ce4fab34b0e/41598_2018_24326_Fig7_HTML.jpg

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