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.
Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States.
Vera
V
Procaccia
Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States; Graduate School of Medicine & Proteo-Medicine Research Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
Hironao
H
Nakayama
Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States.
Akio
A
Shimizu
Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States; Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States. Electronic address: michael.klagsbrun@childrens.harvard.edu.
Michael
M
Klagsbrun
D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism*
C513043:ARHGAP5 protein, human; D001549:Benzamides; D020690:GTPase-Activating Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C108639:SEMA3A protein, human; D040121:Semaphorin-3A; D000068877:Imatinib Mesylate; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases
ABL2; Cell migration; Cytoskeletal collapse; Gleevec; Semaphorin; Stress fibers