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2018 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 5893Article in journal (Refereed) Published
Abstract [en]
Pleiotrophin (PTN) stimulates endothelial cell migration through binding to receptor protein tyrosine phosphatase beta/zeta (RPTP beta/zeta) and alpha(nu)beta(3) integrin. Screening for proteins that interact with RPTP beta/zeta and potentially regulate PTN signaling, through mass spectrometry analysis, identified cyclindependent 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-RPTP beta/zeta interaction and revealed the molecular association of CDK5 and RPTP beta/zeta. In endothelial cells, PTN activates CDK5 in an RPTP beta/zeta- and phosphoinositide 3-kinase (PI3K)-dependent manner. On the other hand, c-Src, alpha(nu)beta(3) 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-alpha] 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 RPTP beta/zeta-dependent manner, regulates PTN-induced cell migration and is an attractive target for the inhibition of PTN pro-angiogenic properties.
Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-352477 (URN)10.1038/s41598-018-24326-x (DOI)000429785900033 ()29651006 (PubMedID)
2018-11-062018-11-062022-09-15Bibliographically approved