BCAR3/AND-34 can signal independent of complex formation with CAS family members or the presence of p130Cas.
BCAR3 binds to the carboxy-terminus of p130Cas, a focal adhesion adapter protein. Both BCAR3 and p130Cas have been linked to resistance to anti-estrogens in breast cancer, Rac activation and cell motility. Using R743A BCAR3, a point mutant that has lost the ability to bind p130Cas, we find that BCAR3-p130Cas complex formation is not required for BCAR3-mediated anti-estrogen resistance, Rac activation or discohesion of epithelial breast cancer cells. Complex formation was also not required for BCAR3-induced lamellipodia formation in BALB/c-3T3 fibroblasts but was required for optimal BCAR3-induced motility. Although both wildtype and R743A BCAR3 induced phosphorylation of p130Cas and the related adapter protein HEF1/NEDD9, chimeric NSP3:BCAR3 experiments demonstrate that such phosphorylation does not correlate with BCAR3-induced anti-estrogen resistance or lamellipodia formation. Wildtype but not R743A BCAR3 induced lamellipodia formation and augmented cell motility in p130Cas(-/-) murine embryonic fibroblasts (MEFs), suggesting that while p130Cas itself is not strictly required for these endpoints, complex formation with other CAS family members is, at least in cells lacking p130Cas. Overall, our work suggests that many, but not all, BCAR3-mediated signaling events in epithelial and mesenchymal cells are independent of p130Cas association. These studies also indicate that disruption of the BCAR3-p130Cas complex is unlikely to reverse BCAR3-mediated anti-estrogen resistance.
Department of Medicine, Boston University School of Medicine and Boston Medical Center, MA, United States.
Pierre
P
Vanden Borre
Richard I
RI
Near
Anthony
A
Makkinje
Gustavo
G
Mostoslavsky
Adam
A
Lerner
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D041702:BALB 3T3 Cells; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D002470:Cell Survival / Q000187:drug effects; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D000077267:Fulvestrant; D017353:Gene Deletion; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C118588:BCAR3 protein, human; C120867:Bcar3 protein, mouse; D050719:Crk-Associated Substrate Protein; D004965:Estrogen Antagonists; D020662:Guanine Nucleotide Exchange Factors; D046912:Multiprotein Complexes; C505592:NEDD9 protein, mouse; D011993:Recombinant Fusion Proteins; D000077267:Fulvestrant; D004958:Estradiol; D051057:Proto-Oncogene Proteins c-akt
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