Plexin-B1 utilizes RHOA and ROK to promote the integrin-dependent activation of AKT and ERK, and endothelial cell motility

doi:10.1074/jbc.M705467200

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Papers In Press, published online ahead of print September 12, 2007
J. Biol. Chem, 10.1074/jbc.M705467200
Submitted on July 3, 2007
Revised on August 31, 2007
Accepted on September 10, 2007

Plexin-B1 utilizes RHOA and ROK to promote the integrin-dependent activation of AKT and ERK, and endothelial cell motility

John R. Basile, Julie Gavard, and J. Silvio Gutkind

Oral and Pharyngeal Cancer Branch, NIDCR, NIH, Bethesda, Maryland MD 20892-4340

Corresponding Author: sg39v{at}nih.gov

The semaphorins are a family of proteins originally identified as axon guiding molecules in the developing nervous system, which have been recently shown to regulate many cellular functions, including motility, in a variety of cell types. We have previously shown that in endothelial cells, Semaphorin 4D acts through its receptor, Plexin-B1, to elicit a pro-angiogenic phenotype that involves the activation of the PI3K-Akt signaling pathway. Here we show through the use of a receptor chimeric approach, Plexin-B1 mutants, and dominant negative and pharmacological inhibitors that this response is dependent upon the activation of RhoA and its downstream target, Rho kinase (ROK). Indeed, we demonstrate that in endothelial cells, Semaphorin 4D promotes the formation of focal adhesion complexes, stress fibers, and the phosphorylation of myosin light chain, a response that was abolished by the use of ROK inhibitors and absent from cells expressing Plexin-B1 mutant constructs incapable of signaling to RhoA. Stress fiber polymerization and contraction are in turn necessary for RhoA-dependent pro-angiogenic signaling through Plexin-B1. Furthermore, we observed that in endothelial cells Plexin-B1 promotes the integrin-mediated activation of Pyk2, resulting in the stimulation of PI3K, Akt and ERK. These findings provide evidence that Plexin-B1 promotes endothelial cell motility through RhoA and ROK by regulating the integrin-dependent signaling networks that result in the activation of PI3K and Akt

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