Abstract
The Src gene product (Src) and the epidermal growth factor receptor (EGFR) are prototypes of oncogene products and function primarily as a cytoplasmic non-receptor tyrosine kinase and a transmembrane receptor tyrosine kinase, respectively. The identification of Src and EGFR, and the subsequent extensive investigations of these proteins have long provided cutting edge research in cancer and other molecular and cellular biological studies. In 1995, we reported that the human epidermoid carcinoma cells, A431, contain a small fraction of Src and EGFR in which these two kinase were in physical association with each other, and that Src phosphorylates EGFR on tyrosine 845 (Y845) in the Src-EGFR complex. Y845 of EGFR is located in the activation segment of the kinase domain, where many protein kinases contain kinase-activating autophosphorylation sites (e.g., cAMP-dependent protein kinase, Src family kinases, transmembrane receptor type tyrosine kinases) or trans-phosphorylation sites (e.g., cyclin-dependent protein kinase, mitogen-activated protein kinase, Akt protein kinase). A number of studies have demonstrated that Y845 phosphorylation serves an important role in cancer as well as normal cells. Here we compile the experimental facts involving Src phosphorylation of EGFR on Y845, by which cell proliferation, cell cycle control, mitochondrial regulation of cell metabolism, gamete activation and other cellular functions are regulated. We also discuss the physiological relevance, as well as structural insights of the Y845 phosphorylation.
Highlights
IntroductionProtein-tyrosine phosphorylation was initially discovered as the catalytic property of the viral oncogene product v-Src gene (Src) [1,2]
Y845, much progress has been made in the recognition that Y845 phosphorylation takes place in a variety of cancerous and normal physiological cell contexts, as well as in the understanding that Y845 phosphorylation plays pivotal roles in these cellular contexts (Figure 2)
Because epidermal growth factor receptor (EGFR) and Src gene (Src) are expressed in almost all normal cells and tissues, the possible impact of their molecular interactions that lead to Y845 phosphorylation may not be limited to the known phenomena described in this review article, but rather spread more to other cellular functions that have not yet been documented
Summary
Protein-tyrosine phosphorylation was initially discovered as the catalytic property of the viral oncogene product v-Src [1,2]. After the discovery of Src and EGFR, much work has focused on understanding how PTKs and their substrates act as a trigger of cellular functions, including malignant cell transformation. These studies include analysis of physical and/or functional interactions, that is, crosstalk, between Src and transmembrane receptor/PTKs such as platelet-derived growth factor receptor [11], Trk/nerve growth factor receptor [12], colony-stimulating factor receptor [13], erbB2/HER2/Neu [14], and EGFR [15,16]. The interaction of Src and EGFR has raised much interest because both are ubiquitously expressed and their co-overexpression and/or mutations have often been found in cancer cells of humans and model animals
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