Cyclin-dependent kinase 5 mediates pleiotrophin-induced endothelial cell migration.
Pleiotrophin (PTN) stimulates endothelial cell migration through binding to receptor protein tyrosine phosphatase beta/zeta (RPTP?/?) and ???3 integrin. Screening for proteins that interact with RPTP?/? 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-RPTP?/? interaction and revealed the molecular association of CDK5 and RPTP?/?. In endothelial cells, PTN activates CDK5 in an RPTP?/?- and phosphoinositide 3-kinase (PI3K)-dependent manner. On the other hand, c-Src, ???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-?]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?/?-dependent manner, regulates PTN-induced cell migration and is an attractive target for the inhibition of PTN pro-angiogenic properties.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Carbazoles, Carrier Proteins, Cell Cycle Proteins, Cell Line, Tumor, Cell Movement, Cyclin-Dependent Kinase 5, Cytokines, Gene Expression Regulation, Guanine, Human Umbilical Vein Endothelial Cells, Humans, Integrin alphaVbeta3, Isoenzymes, Neuroglia, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Protein Binding, Protein Kinase Inhibitors, Rats, Receptor-Like Protein Tyrosine Phosphatases, Class 5, Roscovitine, Signal Transduction
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Carbazoles, Carrier Proteins, Cell Cycle Proteins, Cell Line, Tumor, Cell Movement, Cyclin-Dependent Kinase 5, Cytokines, Gene Expression Regulation, Guanine, Human Umbilical Vein Endothelial Cells, Humans, Integrin alphaVbeta3, Isoenzymes, Neuroglia, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Protein Binding, Protein Kinase Inhibitors, Rats, Receptor-Like Protein Tyrosine Phosphatases, Class 5, Roscovitine, Signal Transduction
Sci Rep
Date: Dec. 12, 2017
PubMed ID: 29651006
View in: Pubmed Google Scholar
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