title: Bcr-Abl induces abnormal cytoskeleton remodeling, beta1 integrin clustering and increased cell adhesion to fibronectin through the Abl interactor 1 pathway.
abstract: Hematopoietic cells isolated from patients with Bcr-Abl-positive leukemia exhibit multiple abnormalities of cytoskeletal and integrin function. These abnormalities are thought to play a role in the pathogenesis of leukemia; however, the molecular events leading to these abnormalities are not fully understood. We show here that the Abi1 pathway is required for Bcr-Abl to stimulate actin cytoskeleton remodeling, integrin clustering and cell adhesion. Expression of Bcr-Abl induces tyrosine phosphorylation of Abi1. This is accompanied by a subcellular translocation of Abi1/WAVE2 to a site adjacent to membrane, where an F-actin-enriched structure containing the adhesion molecules such as beta1-integrin, paxillin and vinculin is assembled. Bcr-Abl-induced membrane translocation of Abi1/WAVE2 requires direct interaction between Abi1 and Bcr-Abl, but is independent of the phosphoinositide 3-kinase pathway. Formation of the F-actin-rich complex correlates with an increased cell adhesion to fibronectin. More importantly, disruption of the interaction between Bcr-Abl and Abi1 by mutations either in Bcr-Abl or Abi1 not only abolished tyrosine phosphorylation of Abi1 and membrane translocation of Abi1/WAVE2, but also inhibited Bcr-Abl-stimulated actin cytoskeleton remodeling, integrin clustering and cell adhesion to fibronectin. Together, these data define Abi1/WAVE2 as a downstream pathway that contributes to Bcr-Abl-induced abnormalities of cytoskeletal and integrin function.
authors: Department of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
authors: Yingzhu
authors: Y
authors: Li
authors: Nancy
authors: N
authors: Clough
authors: Xiaolin
authors: X
authors: Sun
authors: Weidong
authors: W
authors: Yu
authors: Brian L
authors: BL
authors: Abbott
authors: Christopher J
authors: CJ
authors: Hogan
authors: Zonghan
authors: Z
authors: Dai
mesh_terms: D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology*
chemical_list: D005353:Fibronectins; D019012:Integrin beta1; D016044:Fusion Proteins, bcr-abl