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First published online 12 May 2009
doi: 10.1242/jcs.045799

Journal of Cell Science 122, 1812-1822 (2009)
Published by The Company of Biologists 2009
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Research Article

Formation of endothelial lumens requires a coordinated PKC{epsilon}-, Src-, Pak- and Raf-kinase-dependent signaling cascade downstream of Cdc42 activation

Wonshill Koh1, Kamakshi Sachidanandam1, Amber N. Stratman1, Anastasia Sacharidou1, Anne M. Mayo1, Eric A. Murphy2, David A. Cheresh2 and George E. Davis1,3,*

1 Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO 65212, USA
2 Department of Pathology, Moores UCSD Cancer Center, La Jolla, CA 92093, USA
3 Department of Pathology and Anatomical Sciences, School of Medicine, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65212, USA

* Author for correspondence (e-mail: davisgeo{at}health.missouri.edu)

Accepted 26 February 2009

In this study, we present data showing that Cdc42-dependent lumen formation by endothelial cells (ECs) in three-dimensional (3D) collagen matrices involves coordinated signaling by PKC{epsilon} in conjunction with the Src-family kinases (SFKs) Src and Yes. Activated SFKs interact with Cdc42 in multiprotein signaling complexes that require PKC{epsilon} during this process. Src and Yes are differentially expressed during EC lumen formation and siRNA suppression of either kinase, but not Fyn or Lyn, results in significant inhibition of EC lumen formation. Concurrent with Cdc42 activation, PKC{epsilon}- and SFK-dependent signaling converge to activate p21-activated kinase (Pak)2 and Pak4 in steps that are also required for EC lumen formation. Pak2 and Pak4 further activate two Raf kinases, B-Raf and C-Raf, leading to ERK1 and ERK2 (ERK1/2) activation, which all seem to be necessary for EC lumen formation. This work reveals a multicomponent kinase signaling pathway downstream of integrin-matrix interactions and Cdc42 activation involving PKC{epsilon}, Src, Yes, Pak2, Pak4, B-Raf, C-Raf and ERK1/2 to control EC lumen formation in 3D collagen matrices.

Key words: Rho GTPases, PKC{epsilon}, Raf, Lumen formation, Src, Cdc42, Extracellular matrix, Pak


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