Overexpression of both cellular Src (c-Src) and the epidermal growth factor receptor (EGFR) occurs in many of the same human tumors, suggesting that they may functionally interact and contribute to the progression of cancer. Indeed, in murine fibroblasts, overexpression of c-Src has been shown to potentiate the mitogenic and tumorigenic capacity of the overexpressed EGFR. Potentiation correlated with the ability of c-Src to physically associate with the activated EGFR and the appearance of two unique in vivo phosphorylations on the receptor (Tyr-845 and Tyr-1101). Using stable cell lines of C3H10T 1 ⁄2 murine fibroblasts that contain kinase-deficient (K؊) c-Src and overexpressed wildtype EGFR, we show that the kinase activity of c-Src is required for both the biological synergy with the receptor and the phosphorylations on the receptor, but not for the association of c-Src with the receptor. In transient transfection assays, not only epidermal growth factor but also serum-and lysophosphatidic acid-induced DNA synthesis was ablated in a dominant-negative fashion by a Y845F mutant of the EGFR, indicating that c-Src-induced phosphorylation of Y845 is critical for the mitogenic response to both the EGFR and a G protein-coupled receptor (lysophosphatidic acid receptor). Unexpectedly, the Y845F mutant EGFR was found to retain its full kinase activity and its ability to activate the adapter protein SHC and extracellular signal-regulated kinase ERK2 in response to EGF, demonstrating that the mitogenic pathway involving phosphorylation of Y845 is independent of ERK2-activation. The application of these findings to the development of novel therapeutics for human cancers that overexpress c-Src and EGFR is discussed.Considerable evidence has accumulated in recent years to suggest that cellular Src (c-Src) and members of the epidermal growth factor (EGF) receptor (EGFR) family are critical elements in the etiology of multiple human cancers. Both kinases are found overexpressed in many of the same types of tumors, including glioblastomas and carcinomas of the colon, breast, and lung (1-4), raising the question of whether they functionally interact to promote the growth of these malignancies. In breast cancer, overexpression of EGFR family members is estimated to occur in 60% or more of the cases (5), and overexpression of the family member HER2͞NEU, has been associated with a poor prognosis for the disease (6). Recent reports have also described overexpression of c-Src in a significant majority of patients with breast cancer, a frequency that approaches 100% (1). Studies to assess the oncogenic potential of each kinase have shown that the EGFR is tumorigenic when overexpressed in cultured fibroblasts and activated by ligand (7,8), but overexpression of c-Src alone is insufficient for malignant transformation (9, 10).A possible role for c-Src in tumorigenesis was revealed when it was demonstrated in C3H10T 1 ⁄2 murine fibroblasts that co-overexpression of c-Src and the EGFR resulted in a synergistic increase in EGF-ind...
p190 RhoGAP is a tyrosine phosphorylated protein that contains an N-terminal GTP binding domain, a middle domain (MD) that mediates interaction with p120 RasGAP and a C-terminal GTPase-activating protein (GAP) domain that is specific for the Ρ family of small GTPases. Evidence is accumulating to suggest that p190 participates in actin cytoskeleton rearrangements that occur following transformation by v-Src or stimulation by growth factors, and that tyrosine phosphorylation of p190 by Src influences these processes. The current study was performed to establish whether p190RhoGAP directly participates in epidermal growth factor-induced actin stress fiber disassembly and how c-Src is involved in this process. Our results support a model in which the p190 MD negatively regulates the activity of the GAP domain and that c-Src phosphorylation of Y1105 is necessary, but insufficient on its own, for actin stress fiber disassembly.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.