Muthuswamy S K, Muller W J
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada.
Oncogene. 1995 Jul 20;11(2):271-9.
Transgenic mice expressing either the activated or wild type neu oncogene heritably develop metastatic mammary tumors. Tumor development in this transgenic mouse model correlates with activation of the Neu tyrosine kinase. Recently, we have shown that these Neu-induced mammary tumors possess elevated c-Src tyrosine kinase activity. Here, we demonstrate that c-Src requires tyrosine phosphorylated Neu for its ability to associate with Neu in vivo and this association is likely the result of a direct physical binding of c-Src SH2 domain to the tyrosine phosphorylated Neu. By contrast, the c-Src SH2 domain did not interact directly with tyrosine phosphorylated EGFR. Moreover, in established cell lines expressing elevated levels of EGFR, EGF stimulation results in transphosphorylation of Neu and formation of complexes between c-Src and tyrosine phosphorylated Neu. Taken together, these observations suggest that activation of c-Src by these two closely related EGFR family members results from a direct and specific interaction of c-Src with tyrosine phosphorylated Neu.
表达活化型或野生型neu癌基因的转基因小鼠会遗传性地发生转移性乳腺肿瘤。在这个转基因小鼠模型中，肿瘤的发生与Neu酪氨酸激酶的激活相关。最近，我们已经表明，这些由Neu诱导的乳腺肿瘤具有升高的c-Src酪氨酸激酶活性。在这里，我们证明c-Src在体内与Neu结合的能力需要Neu酪氨酸磷酸化，并且这种结合可能是c-Src SH2结构域与酪氨酸磷酸化的Neu直接物理结合的结果。相比之下，c-Src SH2结构域不直接与酪氨酸磷酸化的EGFR相互作用。此外，在表达高水平EGFR的既定细胞系中，EGF刺激导致Neu的转磷酸化以及c-Src与酪氨酸磷酸化的Neu之间形成复合物。综上所述，这些观察结果表明，这两个密切相关的EGFR家族成员对c-Src的激活是由c-Src与酪氨酸磷酸化的Neu直接且特异性的相互作用导致的。
