c-Abl mediates endothelial apoptosis induced by inhibition of integrins alphavbeta3 and alphavbeta5 and by disruption of actin

Blood. 2010 Apr 1;115(13):2709-18. doi: 10.1182/blood-2009-05-223776. Epub 2010 Feb 2.


Inhibition of integrins alphavbeta3 and alphavbeta5 in human brain microvascular endothelial cells (HBMECs) by the function-blocking peptide RGDfV induces loss of spreading on vitronectin, cell detachment, and apoptosis. We demonstrate that cell detachment is not required for apoptosis because plating on bovine serum albumin-blocked poly-L-lysine (allows attachment, but not integrin ligation and cell spreading) also induced apoptosis. Latrunculin B (LatB), which inhibits F-actin polymerization, induced transient loss of HBMEC spreading on vitronectin, but not their detachment, and induced apoptosis despite recovery of cell spreading. However, LatB did not cause apoptosis in 5 tumor cell lines. In HBMECs, both LatB and RGDfV induced transient Y412 and Y245 phosphorylation of endogenous c-Abl, a nonreceptor tyrosine kinase that reciprocally regulates F-actin. LatB also induced nuclear translocation of c-Abl in HBMECs. STI-571 (imatinib), a targeted therapy for BCR-ABL1(+) leukemias and inhibitor of c-Abl, platelet-derived growth factor receptor, and c-Kit, decreased endothelial apoptosis. LatB-induced HBMEC apoptosis, and its inhibition by STI-571 also occurred in a 3-dimensional collagen model, supporting physiologic relevance. Last, siRNA to c-Abl (but not nonspecific siRNA) also inhibited RGDfV- and LatB-induced apoptosis. Thus, endogenous c-Abl mediates endothelial apoptosis induced by inhibition of integrins alphavbeta3/alphavbeta5 or by LatB-induced disruption of F-actin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / drug effects
  • Actin Cytoskeleton / ultrastructure
  • Actins / antagonists & inhibitors*
  • Animals
  • Apoptosis / physiology*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cattle
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Shape / drug effects
  • Culture Media / pharmacology
  • Culture Media, Serum-Free
  • Endothelial Cells / cytology*
  • Endothelial Cells / drug effects
  • Fetal Blood
  • Genes, abl
  • Glioblastoma / pathology
  • Humans
  • Integrin alphaVbeta3 / antagonists & inhibitors*
  • Medulloblastoma / pathology
  • Membrane Potential, Mitochondrial
  • Neuroblastoma / pathology
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors
  • Proto-Oncogene Proteins c-abl / physiology*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, Vitronectin / antagonists & inhibitors*
  • Thiazolidines / pharmacology


  • Actins
  • Bridged Bicyclo Compounds, Heterocyclic
  • Culture Media
  • Culture Media, Serum-Free
  • Integrin alphaVbeta3
  • RNA, Small Interfering
  • Receptors, Vitronectin
  • Thiazolidines
  • integrin alphaVbeta5
  • Proto-Oncogene Proteins c-abl
  • latrunculin B