Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia
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Bosutti-2013-Targeting p35_Cdk5 S.pdf
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Author(s)
Bosutti, Alessandra
Qi, Jie
Pennucci, Roberta
Bolton, David
Matou, Sabine
Ali, Kamela
Tsai, Li-Huei
Krupinski, Jerzy
Petcu, Eugene B.
Montaner, Joan
Date Issued
September 2013
Journal
PLoS ONE
Publisher
Public Library of Science
Citation
Bosutti, Alessandra, Jie Qi, Roberta Pennucci, David Bolton, Sabine Matou, Kamela Ali, Li-Huei Tsai, et al. “Targeting p35/Cdk5 Signalling via CIP-Peptide Promotes Angiogenesis in Hypoxia.” Edited by Alain-Pierre Gadeau. PLoS ONE 8, no. 9 (September 30, 2013): e75538.
Version
Final published version
Abstract
Cyclin-dependent kinase-5 (Cdk5) is over-expressed in both neurons and microvessels in hypoxic regions of stroke tissue and has a significant pathological role following hyper-phosphorylation leading to calpain-induced cell death. Here, we have identified a critical role of Cdk5 in cytoskeleton/focal dynamics, wherein its activator, p35, redistributes along actin microfilaments of spreading cells co-localising with p[subscript (Tyr15)]Cdk5, talin/integrin beta-1 at the lamellipodia in polarising cells. Cdk5 inhibition (roscovitine) resulted in actin-cytoskeleton disorganisation, prevention of protein co-localization and inhibition of movement. Cells expressing Cdk5 (D144N) kinase mutant, were unable to spread, migrate and form tube-like structures or sprouts, while Cdk5 wild-type over-expression showed enhanced motility and angiogenesis in vitro, which was maintained during hypoxia. Gene microarray studies demonstrated myocyte enhancer factor (MEF2C) as a substrate for Cdk5-mediated angiogenesis in vitro. MEF2C showed nuclear co-immunoprecipitation with Cdk5 and almost complete inhibition of differentiation and sprout formation following siRNA knock-down. In hypoxia, insertion of Cdk5/p25-inhibitory peptide (CIP) vector preserved and enhanced in vitro angiogenesis. These results demonstrate the existence of critical and complementary signalling pathways through Cdk5 and p35, and through which coordination is a required factor for successful angiogenesis in sustained hypoxic condition.
MIT Department
Picower Institute for Learning and Memory
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DOI of Published Version
https://doi.org/10.1371/journal.pone.0075538
