Breast cancer antiestrogen resistance 3-p130Casinteractions promote adhesion disassembly and invasion in breast cancer cells.
Adhesion turnover is critical for cell motility and invasion. We previously demonstrated that the adaptor molecule breast cancer antiestrogen resistance 3 (BCAR3) promotes adhesion disassembly and breast tumor cell invasion. One of two established binding partners of BCAR3 is the adaptor molecule, p130Cas. In this study, we sought to determine whether signaling through the BCAR3-Cas complex was responsible for the cellular functions of BCAR3. We show that the entire pool of BCAR3 is in complex with Cas in invasive breast tumor cells and that these proteins colocalize in dynamic cellular adhesions. Although accumulation of BCAR3 in adhesions did not require Cas binding, a direct interaction between BCAR3 and Cas was necessary for efficient dissociation of BCAR3 from adhesions. The dissociation rates of Cas and two other adhesion molecules, α-actinin and talin, were also significantly slower in the presence of a Cas-binding mutant of BCAR3, suggesting that turnover of the entire adhesion complex was delayed under these conditions. As was the case for adhesion turnover, BCAR3-Cas interactions were found to be important for BCAR3-mediated breast tumor cell chemotaxis toward serum and invasion in Matrigel. Previous work demonstrated that BCAR3 is a potent activator of Rac1, which in turn is an important regulator of adhesion dynamics and invasion. However, in contrast to wild-type BCAR3, ectopic expression of the Cas-binding mutant of BCAR3 failed to induce Rac1 activity in breast cancer cells. Together, these data show that the ability of BCAR3 to promote adhesion disassembly, tumor cell migration and invasion, and Rac1 activity is dependent on its ability to bind to Cas. The activity of BCAR3-Cas complexes as a functional unit in breast cancer is further supported by the co-expression of these molecules in multiple subtypes of human breast tumors.
Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
A M
AM
Cross
Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
A L
AL
Wilson
Fujifilm Diosynth Biotechnologies, USA, Inc., Cary, NC, USA.
M S
MS
Guerrero
Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
K S
KS
Thomas
Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
A I
AI
Bachir
Department of Biology, James Madison University, Harrisonburg, VA, USA.
K E
KE
Kubow
Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
A R
AR
Horwitz
Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
A H
AH
Bouton
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding
D048868:Adaptor Proteins, Signal Transducing; C118588:BCAR3 protein, human; D002352:Carrier Proteins; D050719:Crk-Associated Substrate Protein; D020662:Guanine Nucleotide Exchange Factors; D046912:Multiprotein Complexes