BCAR3 regulates Src/p130 Cas association, Src kinase activity, and breast cancer adhesion signaling.
The nonreceptor protein-tyrosine kinase c-Src is frequently overexpressed and/or activated in a variety of cancers, including those of the breast. Several heterologous binding partners of c-Src have been shown to regulate its catalytic activity by relieving intramolecular autoinhibitory interactions. One such protein, p130(Cas) (Cas), is expressed at high levels in both breast cancer cell lines and breast tumors, providing a potential mechanism for c-Src activation in breast cancers. The Cas-binding protein BCAR3 (breast cancer antiestrogen resistance-3) is expressed at high levels in invasive breast cancer cell lines, and this molecule has previously been shown to coordinate with Cas to increase c-Src activity in COS-1 cells. In this study, we show for the first time using gain- and loss-of-function approaches that BCAR3 regulates c-Src activity in the endogenous setting of breast cancer cells. We further show that BCAR3 regulates the interaction between Cas and c-Src, both qualitatively as well as quantitatively. Finally, we present evidence that the coordinated activity of these proteins contributes to breast cancer cell adhesion signaling and spreading. Based on these data, we propose that the c-Src/Cas/BCAR3 signaling axis is a prominent regulator of c-Src activity, which in turn controls cell behaviors that lead to aggressive and invasive breast tumor phenotypes.
Schuh
Natasha R
NR
Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Guerrero
Michael S
MS
Schrecengost
Randy S
RS
Bouton
Amy H
AH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D019556:COS Cells; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D010766:Phosphorylation / Q000502:physiology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C118588:BCAR3 protein, human; D050719:Crk-Associated Substrate Protein; D005353:Fibronectins; D020662:Guanine Nucleotide Exchange Factors; D034741:RNA, Small Interfering; D014443:Tyrosine; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases