Cellular Functions Regulated by Phosphorylation of EGFR on Tyr845

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.

Modulation of focal adhesion constituents and their down-stream events by EGF: On the cross-talk of integrins and growth factor receptors

“…Though dispensable for ligand-induced activation, Tyr845 has been proven to be the primary site for receptor transactivation via Src [17,18,20]. Against this background, the enhanced EGFR activity detected after EGF treatment in the corneal cells appears likely to represent a Src-mediated transphosphorylation and/or transactivation (Fig.…”

“…This signaling includes pathways and pathwayimmanent target molecules which direct cell behavioral aspects such as proliferation, differentiation and motility. Several routes of activation have been described for MAP-kinases and p190RhoGAP in the context of GFRs [20] and FAs [45,46]. Moreover, MAP-kinase signaling and p190RhoGAP phosphorylation were also shown to emerge from Src [47,48].…”

“…By using this modus operandi, we analyzed the EGF response by firstly focusing on the EGFR itself. After administration of soluble EGF, ligand-activated EGFR is usually autophosphorylated at multiple tyrosine (Tyr) residues, which among others include Tyr992, Tyr1068, Tyr1086, Tyr1148, and Tyr1173 ( [31] for review see [20]). While Tyr-residue-autophosphorylation provides docking sites for EGFR-interacting signaling molecules harboring a phosphotyrosine binding sequence, serine (Ser) residue phosphorylation, for example Ser1142 [31], appears to be of regulatory importance, due to its role in receptor dimerization, catalytic activity, and turn-over [32].…”

“…Signaling cascades emerging from mechanotransducing FA-innate integrin receptors as well as growth factor receptors (GFR) govern cell behavior [20,43,44]. This signaling includes pathways and pathwayimmanent target molecules which direct cell behavioral aspects such as proliferation, differentiation and motility.…”

“…While Tyr-residue-autophosphorylation provides docking sites for EGFR-interacting signaling molecules harboring a phosphotyrosine binding sequence, serine (Ser) residue phosphorylation, for example Ser1142 [31], appears to be of regulatory importance, due to its role in receptor dimerization, catalytic activity, and turn-over [32]. In addition to these common activation sites, another phosphorylation site, represented by Tyr845 reflects the site through which EGFR has originally been found to be transphosphorylated by the cytoplasmic non-receptor tyrosine kinase Src ( [33][34][35] for review see [20]). This transphosphorylation is facilitated through Src-EGFR-complex formation and thus physical interaction of both molecules [36].…”