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

Lampropoulou, E, Logoviti, I, Koutsioumpa, M, Hatziapostolou, M ORCID: https://orcid.org/0000-0003-2493-7028, Polytarchou, C ORCID: https://orcid.org/0000-0002-1948-7934, Skandalis, SS, Hellman, U, Fousteris, M, Nikolaropoulos, S, Choleva, E, Lamprou, M, Skoura, A, Megalooikonomou, V and Papadimitriou, E, 2018. Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration. Scientific Reports, 8: 5893. ISSN 2045-2322

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Abstract

Pleiotrophin (PTN) stimulates endothelial cell migration through binding to receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and ανβ3 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, ανβ3 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.

Item Type:	Journal article
Publication Title:	Scientific Reports
Creators:	Lampropoulou, E., Logoviti, I., Koutsioumpa, M., Hatziapostolou, M., Polytarchou, C., Skandalis, S.S., Hellman, U., Fousteris, M., Nikolaropoulos, S., Choleva, E., Lamprou, M., Skoura, A., Megalooikonomou, V. and Papadimitriou, E.
Publisher:	Nature Publishing Group
Date:	12 April 2018
Volume:	8
ISSN:	2045-2322
Identifiers:	Number Type 10.1038/s41598-018-24326-x DOI 24326 Publisher Item Identifier
Rights:	Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	19 Apr 2018 08:01
Last Modified:	14 May 2018 10:58
URI:	https://irep.ntu.ac.uk/id/eprint/33276

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