Formation of endothelial lumens requires a coordinated PKCϵ-, Src-, Pak- and Raf-kinase-dependent signaling cascade downstream of Cdc42 activation
Open Access
- 1 June 2009
- journal article
- Published by The Company of Biologists in Journal of Cell Science
- Vol. 122 (11), 1812-1822
- https://doi.org/10.1242/jcs.045799
Abstract
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 PKCϵ in conjunction with the Src-family kinases (SFKs) Src and Yes. Activated SFKs interact with Cdc42 in multiprotein signaling complexes that require PKCϵ 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, PKCϵ- 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 PKCϵ, Src, Yes, Pak2, Pak4, B-Raf, C-Raf and ERK1/2 to control EC lumen formation in 3D collagen matrices.Keywords
This publication has 90 references indexed in Scilit:
- The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPasesNature Medicine, 2009
- Signaling crossroads: The function of Raf kinase inhibitory protein in cancer, the central nervous system and reproductionCellular Signalling, 2008
- Single and Combined Silencing of ERK1 and ERK2 Reveals Their Positive Contribution to Growth Signaling Depending on Their Expression LevelsMolecular and Cellular Biology, 2008
- Raf kinases: Function, regulation and role in human cancerBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2007
- Phosphorylation of RhoGDI by Src Regulates Rho GTPase Binding and Cytosol-Membrane CyclingMolecular Biology of the Cell, 2006
- A Dimeric Kinase Assembly Underlying Autophosphorylation in the p21 Activated KinasesJournal of Molecular Biology, 2006
- PKCɛ-mediated phosphorylation of vimentin controls integrin recycling and motilityThe EMBO Journal, 2005
- The RAF proteins take centre stageNature Reviews Molecular Cell Biology, 2004
- Tube Morphogenesis: Making and Shaping Biological TubesCell, 2003
- Role of c-Fyn in FGF-2-Mediated Tube-like Structure Formation by Murine Brain Capillary Endothelial CellsBiochemical and Biophysical Research Communications, 2002