Gleevec/imatinib, an ABL2 kinase inhibitor, protects tumor and endothelial cells from semaphorin-induced cytoskeleton collapse and loss of cell motility.

Class 3 semaphorins are axonal guidance mediators and regulators of angiogenesis and tumor progression. Semaphorin 3A and 3F (SEMA3A&F) act by depolymerizing F-actin, resulting in cytoskeleton collapse. A key signaling step is that SEMA3A&F activates ABL2 tyrosine kinase, which activates p190RhoGAP, which in turn inactivates RhoA, thereby diminishing stress fiber formation and ensuing cell migration. We now demonstrate that Gleevec (imatinib, STI571), an ABL2 tyrosine kinase inhibitor, abrogates SEMA3A&F-induced stress fiber loss in glioblastoma cells and endothelial cells and diminishes their ability to inhibit migration. On the other hand, Sutent (sunitinib), a receptor tyrosine kinase inhibitor, did not rescue SEMA3A&F-induced collapsing activity. These results describe a novel property of Gleevec, its ability to antagonize semaphorins.