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First published online 27 March 2007
doi: 10.1242/jcs.03430

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Bcr-Abl induces abnormal cytoskeleton remodeling, 1 integrin clustering and increased cell adhesion to fibronectin through the Abl interactor 1 pathway

Yingzhu Li¹, Nancy Clough¹, Xiaolin Sun¹, Weidong Yu¹, Brian L. Abbott¹, Christopher J. Hogan^1,2 and Zonghan Dai^1,2,3,*,

¹ Department of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA
² University of Colorado Cancer Center, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA
³ Cell and Developmental Biology, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA

Author for correspondence (e-mail: zonghan.dai{at}ttuhsc.edu)

Accepted 22 February 2007

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 1-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.

Key words: Abi1, Bcr-Abl, WAVE2, Actin cytoskeleton, 1-integrin, Cell adhesion

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