EGF receptor, phosphorylation

Goldkom, T. et al., EGF-receptor phosphorylation and signaling are targeted by H202 redox stress, Hw. J. Respir. Cell Mol Biol, 19,786, 1998. 

Figure 2 The surface of activated human N-ezrin is shown (PDB accession no 1NI2 The AGE binding site of ezrin (on the right) is distant from Tyrl45, the EGF receptor phosphorylation site (on the left). The figure was prepared using UCSF Chimera, alpha version 1.4...

The growth requirement for EGF is a good example in this regard. EGF stimulates the growth of many different types of animal cells in culture. In order to initiate the growth response, EGF interacts with specific EGF receptors localized in the plasma membrane, activating a tyrosine-specific protein kinase, which is an intrinsic part of the receptor (Figure 12). As a consequence, specific proteins are phosphorylated at tyrosine residues, and some of these proteins (which are also... 

Single protein kinases such as PKA, PKC, and Ca +-calmodulin (CaM)-kinases, which result in the phosphorylation of serine and threonine residues in target proteins, play a very important role in hormone action. The discovery that the EGF receptor contains an intrinsic tyrosine kinase activity that is activated by the binding of the hgand EGF was an important breakthrough. The insuhn and IGF-I receptors also contain intrinsic... 

All RTKs contain between one and three tyrosines in the kinase activation loop, which is composed of subdomains VII and VIII of the protein kinase catalytic core. Phosphorylation of these tyrosines has been shown to be critical for stimulation of catalytic activity and biological function for a number of RTKs, including insulin receptor, FGF receptor, VEGF receptor, PDGF receptor, Met (hepatocyte growth factor receptor), and TrkA (NGF receptor). A major exception is the EGF receptor, for which autophosphorylation of a conserved tyrosine in the activation loop does not seem to be involved in signaling. Substitution of tyrosine with phenylalanine has no effect on RTK activity or downstream signals. 

Bowtell, D. D., and W. Y. Langdon. The protein product of the c-cbl oncogene rapidly complexes with the EGF receptor and is tyrosine phosphorylated following EGF stimulation. Oncogene. 11 1561-1567.1995. 

Fukazawa, T., S. Miyake, V. Band, and H. Band. Tyrosine phosphorylation of Cbl upon epidermal growth factor (EGF) stimulation and its association with EGF receptor and downstream signaling proteins. J Biol Chem. 271 14554-14559.1996. 

Galisteo, M. L., I. Dikic, A. G. Batzer, W. Y. Langdon, and J. Schlessinger. Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation. J Biol Chem. 270 20242-20245.1995. 

Cross-phosphorylation of the EGF receptor has also been observed dining the process of activation of cytokine receptors, whereby crosstalk with receptor tyrosine kinases is possible. 

Mechanism of activation of the epidermal growth factor (EGF) receptor, a representative receptor tyrosine kinase. The receptor polypeptide has extracellular and cytoplasmic domains, depicted above and below the plasma membrane. Upon binding of EGF (circle), the receptor converts from its inactive monomeric state (/eft) to an active dimeric state (right), in which two receptor polypeptides bind noncovalently. The cytoplasmic domains become phosphorylated (P) on specific tyrosine residues (Y) and their enzymatic activities are activated, catalyzing phosphorylation of substrate proteins (S). 

Fig. 6.4 Proposed scheme for ATj-mediated transactivation of the EGF receptor and the subsequent activation of ERK1/2. The interaction of angiotensin II with the ATi receptor stimulates several pathways that result in the transactivation of the EGF receptor. In one pathway, phospholipase C (PLC) is activated, which in turn promotes the production of reactive oxygen species (ROS). ATj receptor activation also elevates [Ca2+]j, contributing to the stimulation of a Ca2+-dependent tyrosine kinase, of which Src and proline-rich tyrosine kinase-2 (Pyk2) are the preferred targets. Both ROS and the Ca2+-dependent tyrosine kinase activate a metalloprotease, presumably ADAM17, which proteolytically activates the EGF ligand. The Ca2+-dependent tyrosine kinase, as well as a Ca2+-independent kinase, also phosphorylate the EGF receptor. The activation of the EGF receptor triggers a cascade leading to the activation of ERK1/2. EGF receptor transactivation also proceeds via a G-protein-independent pathway (see text).

Based on the evidence that several antioxidants inhibit angiotensin II-mediated phosphorylation of the EGF receptor (Ushio-Fukai et al. 2001) while H2O2 induces its phosphorylation, it has been postulated that oxidative stress is an early and necessary event in the transactivation of the EGF receptor (Zhang et al. 2005). A likely site of reactive oxygen species (ROS) action is the inhibition of a protein tyrosine... 

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