Src Family Kinases Promote Vessel Stability by Antagonizing the Rho/ROCK Pathway

Eunok Im,Andrius Kazlauskas

doi:10.1074/jbc.m702637200

Abstract

Src family kinases (SFKs) are one of the signaling enzymes that contribute to angiogenesis, but their precise input to the various phases of the angiogenic program has not been defined. Using an in vitro model system, we discovered that SFKs promoted the formation of tubes and prevented their regression. They suppressed regression by activating the ERK pathway that antagonized the Rho/ROCK pathway, which was essential for regression. These studies reveal that SFKs contribute to several phases of the angiogenic program and identify the downstream effectors by which SFKs stabilize tubes.

Highlights

The realization that effectively silencing vascular endothelial growth factor (VEGF) is likely to have undesirable side effects [5, 6] has catalyzed research to identify signaling enzymes that govern the various phases of the angiogenic program
We previously reported that PI3K was required for tube formation in an in vitro angiogenesis assay [13]
These studies relied in part on the Tyr-740/Tyr-751 platelet-derived growth factor receptors (PDGFR)␤ that recruits and activates two signaling enzymes known to be involved with angiogenesis, PI3K and SFKs

Summary

Introduction

The realization that effectively silencing VEGF is likely to have undesirable side effects [5, 6] has catalyzed research to identify signaling enzymes that govern the various phases of the angiogenic program. We report that SFKs promote tube formation and antagonize regression. These studies relied in part on the Tyr-740/Tyr-751 PDGFR␤ that recruits and activates two signaling enzymes known to be involved with angiogenesis, PI3K and SFKs. In this study we used molecular and pharmacological approaches to assess the role of SFKs in tube formation and regression. The low, endogenous level of PDGF was insufficient to induce tube formation in cells expressing the ␣/␤ SFKϩ chimera (which activates SFKs [23] (supplemental Fig. S1B)).

Results

Conclusion