POTENTIATION OF EPIDERMAL GROWTH-FACTOR RECEPTOR-MEDIATED ONCOGENESIS BY C-SRC - IMPLICATIONS FOR THE ETIOLOGY OF MULTIPLE HUMAN CANCERS
POTENTIATION OF EPIDERMAL GROWTH-FACTOR RECEPTOR-MEDIATED ONCOGENESIS BY C-SRC - IMPLICATIONS FOR THE ETIOLOGY OF MULTIPLE HUMAN CANCERS
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DOI：
10.1073/pnas.92.15.6981
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发表时间：
1995-07-18
影响因子：
11.1
通讯作者：
PARSONS, SJ
中科院分区：
文献类型：
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作者：
MAA, MC;LEU, TH;PARSONS, SJ
c-Src是一种非转化酪氨酸激酶，参与多种多肽生长因子受体（包括表皮生长因子受体（EGFR））介导的信号传导事件。EGFR的过表达和持续的配体刺激导致体外细胞的形态学转化和体内肿瘤的发展。在多种人类恶性肿瘤中发现c-Src和EGFR的水平升高，提出了c-Src在肿瘤发生期间是否可以与EGFR功能性合作的问题。为了解决这个问题，我们产生了c-Src/EGFR双过表达细胞，并将它们的增殖和生物化学特征与单过表达细胞和对照细胞的增殖和生物化学特征进行了比较，我们发现在表达高水平受体的细胞中，c-Src增强DNA合成，在软琼脂中的生长和裸鼠中的肿瘤形成。生长增强与c-Src和活化的EGFR之间的异源复合物的形成、受体上明显的酪氨酰磷酸化的出现以及受体底物磷酸化的增强相关。这些发现表明c-Src能够增强受体介导的肿瘤发生，并且表明c-Src和EGFR之间的协同作用可能有助于多种人类肿瘤中更具侵袭性的表型。
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.