Abstract
Overexpression or increased activity of cellular Src (c-Src) is frequently detected in human breast cancer, implicating involvement of c-Src in the etiology of breast carcinomas. Curiously, overexpression of c-Src in tissue culture cells results in a weakly or non-transforming phenotype, indicating that it alone is not sufficient for oncogenesis. However, the protein has been demonstrated to potentiate mitogenic signals from transmembrane receptors. This report investigates the requirement for c-Src in breast cancer as a transducer and integrator of anchorage-dependent and -independent growth signals by utilizing the Src family pharmacological inhibitors, PP1 and PP2, or stable overexpression of the catalytically inactive c-Src mutant (K- c-Src). Both methods of inhibiting endogenous c-Src diminished formation of soft agar colonies and tumors in nude mice. The majority of the dominant-negative activity of K- c-Src was mapped to the Src homology 2 (SH2) domain and C-terminal half of the molecule, but not to the Unique domain, Src homology 3 (SH3) domain, or the N-terminal half of K- c-Src. Further analysis of the C terminus revealed that its ability to inhibit growth localized to the N-terminal lobe (N-lobe) of the catalytic region. These results underscore the requirement for c-Src to maintain the oncogenic phenotype of breast cancer cells and suggest that c-Src may be manipulated to inhibit cell growth by the direct disruption of its catalytic activity or the introduction of either the SH2 domain or the N-lobe of K- c-Src.
Highlights
Overexpression of c-Src alone is insufficient, c-Src appears to promote the mitogenic and tumorigenic properties of other cellular proteins
C-Src potentiates EGFinduced anchorage-dependent and -independent growth in murine fibroblasts by mediating phosphorylation of the epidermal growth factor receptor (EGFR) at tyrosine 845 (Tyr-845) [5,6,7, 7]. c-Src has been demonstrated to cooperate with Gprotein-coupled receptors [8], platelet-derived growth factor receptor [9], colony-stimulating factor-1 receptor [10], and inmation of soft agar colonies and tumors in nude mice. tegrins [11] by facilitating proliferative signals from these varThe majority of the dominant-negative activity of K؊ ious receptors through enhancement of p85 phosphatidylinosic-Src was mapped to the Src homology 2 (SH2) domain and C-terminal half of the molecule, but not to the Unique domain, Src homology 3 (SH3) domain, or the N-terminal half of K؊ c-Src
The MDA-MB-468 stable clone (468 KϪ8) with 10-fold higher KϪ c-Src overexpression than endogenous c-Src had a significantly lower tumor volume compared with either the parental cell line or the stable clone with only a 4-fold increased level of KϪ c-Src (Table I). These results demonstrated that the catalytic activity of c-Src is necessary for maintaining the tumorigenic phenotype of breast cancer cells
Summary
Overexpression of c-Src alone is insufficient, c-Src appears to promote the mitogenic and tumorigenic properties of other cellular proteins. Tegrins [11] by facilitating proliferative signals from these varThe majority of the dominant-negative activity of K؊ ious receptors through enhancement of p85 phosphatidylinosic-Src was mapped to the Src homology 2 (SH2) domain and C-terminal half of the molecule, but not to the Unique domain, Src homology 3 (SH3) domain, or the N-terminal half of K؊ c-Src. Further analysis of the C terminus revealed that its ability to inhibit growth localized to the N-terminal lobe (N-lobe) of the catalytic region. Further analysis of the C terminus revealed that its ability to inhibit growth localized to the N-terminal lobe (N-lobe) of the catalytic region These results underscore the requirement for c-Src to maintain the oncogenic phenotype of breast cancer cells and suggest that c-Src may be manipulated to inhibit cell growth by the direct disruption of its catalytic activity or the introduction of either the SH2 domain or the N-lobe of K؊ c-Src. tol 3-kinase, RasGAP, Shc, and phospholipase C␥ tyrosine phosphorylation [12,13,14].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
