Maa M C, Leu T H, McCarley D J, Schatzman R C, Parsons S J
Department of Microbiology and Cancer Center, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6981-5. doi: 10.1073/pnas.92.15.6981.
c-Src is a nontransforming tyrosine kinase that participates in signaling events mediated by a variety of polypeptide growth factor receptors, including the epidermal growth factor receptor (EGFR). Overexpression and continual ligand stimulation of the EGFR results in morphological transformation of cells in vitro and tumor development in vivo. Elevated levels of c-Src and the EGFR are found in a variety of human malignancies, raising the question of whether c-Src can functionally cooperate with the EGFR during tumorigenesis. To address this issue, we generated c-Src/EGFR double overexpressors and compared their proliferative and biochemical characteristics to those of single overexpressors and control cells. We found that in cells expressing high levels of receptor, c-Src potentiated DNA synthesis, growth in soft agar, and tumor formation in nude mice. Growth potentiation was associated with the formation of a heterocomplex between c-Src and activated EGFR, the appearance of a distinct tyrosyl phosphorylation on the receptor, and an enhancement of receptor substrate phosphorylation. These findings indicate that c-Src is capable of potentiating receptor-mediated tumorigenesis and suggest that synergism between c-Src and the EGFR may contribute to a more aggressive phenotype in multiple human tumors.
c-Src是一种非转化性酪氨酸激酶，参与由多种多肽生长因子受体介导的信号转导事件，包括表皮生长因子受体（EGFR）。EGFR的过表达和持续的配体刺激导致体外细胞形态转化和体内肿瘤发展。在多种人类恶性肿瘤中发现c-Src和EGFR水平升高，这就提出了一个问题，即c-Src在肿瘤发生过程中是否能与EGFR在功能上协同作用。为了解决这个问题，我们构建了c-Src/EGFR双过表达细胞，并将它们的增殖和生化特性与单过表达细胞和对照细胞进行比较。我们发现，在高表达受体的细胞中，c-Src增强了DNA合成、软琼脂中的生长以及裸鼠体内的肿瘤形成。生长增强与c-Src和活化的EGFR之间形成异源复合物、受体上出现明显的酪氨酸磷酸化以及受体底物磷酸化增强有关。这些发现表明，c-Src能够增强受体介导的肿瘤发生，并提示c-Src与EGFR之间的协同作用可能导致多种人类肿瘤中更具侵袭性的表型。
