ABL2/ARG tyrosine kinase mediates SEMA3F-induced RhoA inactivation and cytoskeleton collapse in human glioma cells.

Abstract

Class three semaphorins (SEMAs) were originally shown to be mediators of axon guidance that repelled axons and collapsed growth cones, but it is now evident that SEMA3F, for example, has similar effects on tumor cells and endothelial cells (EC). In both human U87MG glioma cells and human umbilical vein EC, SEMA3F induced rapid cytoskeletal collapse, suppressed cell contractility, decreased phosphorylation of cofilin, and inhibited cell migration in culture. Analysis of the signaling pathways showed that SEMA3F formed a complex with NRP2 (neuropilin-2) and plexin A1. These interactions eventually led to inactivation of the small GTPase, RhoA, which is necessary for stress fiber formation and cytoskeleton integrity. A novel upstream RhoA mediator was shown to be ABL2, also known as ARG, a membrane-anchored nonreceptor tyrosine kinase. Within minutes after the addition of SEMA3F, ABL2 directly bound plexin A1 but not to a plexin A1 mutant lacking the cytoplasmic domain. In addition, ABL2 phosphorylated and thereby activated p190RhoGAP, which inactivated RhoA (GTP to GDP), resulting in cytoskeleton collapse and inhibition of cell migration. On the other hand, cells overexpressing an ABL2 inactive kinase mutant or treated with ABL2 small interfering RNA did not inactivate RhoA. Cells treated with p190RhoGAP small interfering RNA also did not inactivate RhoA. Together, these results suggested that ABL2/ARG is a novel mediator of SEMA3F-induced RhoA inactivation and collapsing activity.

• Authors: Akio Shimizu, Akiko Mammoto, Joseph E Italiano Jr, Elke Pravda, Andrew C Dudley, Donald E Ingber, Michael Klagsbrun
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 40 Pg. 27230-8 (Oct 03 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18660502 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• GTPase-Activating Proteins
• Membrane Proteins
• Nerve Tissue Proteins
• Neuropilin-2
• PLXNA1 protein, human
• Receptors, Cell Surface
• SEMA3F protein, human
• rho GTPase-activating protein
• RHOA protein, human
• Proto-Oncogene Proteins c-abl
• rhoA GTP-Binding Protein

Topics

• Animals
• Cell Line, Tumor
• Cytoskeleton (genetics, metabolism)
• Endothelial Cells (metabolism)
• GTPase-Activating Proteins (genetics, metabolism)
• Glioma (genetics, metabolism)
• Humans
• Membrane Proteins (genetics, metabolism)
• Mutation
• Nerve Tissue Proteins (genetics, metabolism)
• Neuropilin-2 (genetics, metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-abl (genetics, metabolism)
• Receptors, Cell Surface (genetics, metabolism)
• Signal Transduction (genetics)
• Swine
• rhoA GTP-Binding Protein (genetics, metabolism)