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Circulation. 2006;114:II_297

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(Circulation. 2006;114:II_297.)
© 2006 American Heart Association, Inc.

Growth Factors, Cytokines, Signal Transduction VIII

Abstract 1535: PB1 Domain Mediated PKCz and p62 Interaction Regulates Flow-Induced ERK5 Activation

Gwenaele garin1; Junichi Abe1; Chen Yan1; Weimin Liu2; Andrew Newby3; Arshad Rahman4; Bradford Berk5

1 Cardiovascualr Rsch Institute U, Rochester, NY
2 Cardiovascualr Rsch Institute U, Richmond, NY
3 Heart Institute, Bristol, United Kingdom
4 Univ of Rochester, Rochester, NY
5 Cardiovascualr Rsch Institute U, Rochester, NY

ERK5 mediates several flow-dependent endothelial cell (EC) functions including cell survival and gene expression. The upstream regulators of ERK5 stimulated by flow are poorly characterized. A protein-protein interaction domain termed PB1 was identified by proteomics as potentially involved in ERK5 activation, since MEK5 and MEKK3 (known ERK5 activators) contain PB1 domains. Therefore we hypothesized that PKC{zeta} and p62, PB1 containing proteins prominent in EC, would regulate ERK5. PKC{zeta} was phosphorylated and activated by shear stress (12 dyn/cm2, 2-fold increase at 10 min) in EC. Decreasing PKC{zeta} expression by siRNA reduced significantly (50%) flow-induced ERK5 activation (measured by both kinase and luciferase assays). Inhibiting PKC{zeta} activity with an adenoviral dominant-negative PKC{zeta} blocked ERK5 activation. PKC{zeta} signals downstream of MEK5 since PKC{zeta} siRNA blocked effects of overexpressed constitutive active (CA) MEK5 on ERK5 activity. In contrast, PKC{zeta} wild type overexpression increased CA-MEK5 activation of ERK5. These observations demonstrate a positive role for PKC{zeta} in ERK5 regulation. Assembly of a MEKK3-MEK5-ERK5-PKC{zeta} signalosome likely involves a scaffold protein. Because p62 is a well-known PB1 scaffold, we studied its interactions with ERK5 and PKC{zeta} in EC. We found that p62 and ERK5 interacted basally and flow decreased the ERK5/p62 interaction. Overexpressing p62 wild type inhibited flow-induced ERK5 activity and increased EC apoptosis. In response to flow (12 dyn/cm2, 10 min), p62 associated with PKC{zeta}. We propose that the scaffold p62 binds and inhibits ERK5 basally. Flow activates PKC{zeta} which now recruits p62 and allows MEK5 to bind and activate ERK5. This study defines flow-mediated interactions between PB1-domain containing proteins that control ERK5 activity, and suggests that PKC{zeta} and p62 are novel regulators of EC survival and gene expression.





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