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Ligand binding to the epidermal growth factor receptor (EGF R) induces receptor homo- and/or heterodimerization and the subsequent phosphorylation of specific tyrosine residues in the cytoplasmic domain of the EGF R. The phosphorylated receptor then recruits adaptor proteins and enzymes to transmit signals from the receptor through signaling pathways to the nucleus, regulating diverse biological functions such as cell proliferation, differentiation, migration, and apoptosis (Morandell et al. 2008; Yarden and Sliwkowski 2001).
More than one hundred proteins have been reported in the literature to interact with EGF R (Morandell et al. 2008). The following summary describes major EGF R tyrosine phosphorylation sites, as well as selected adaptors and signaling proteins.
The majority of tyrosine sites of the EGF R are autophosphorylated. Tyr920 phosphorylation of EGF R acts as a docking site for the phosphatidylinositol 3-kinase regulatory subunit alpha (p85) (Stover et al. 1995). Tyr992 phosphorylated EGF R binds 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 (PLCγ) (Rotin et al. 1992), resulting in activation of PLCγ-mediated downstream signaling (Emlet et al. 1997). This site is dephosphorylated by the tyrosine-protein phosphatase non-receptor type 11 (SHP2) (Agazie and Hayman 2003). In addition, the guanine nucleotide exchange factor (VAV2) SRC homology 2 domain preferentially binds to the Tyr992 site (Tamas et al. 2003). The E3 ubiquitin ligase, CBL, binds to Tyr1045 upon its phosphorylation (Levkowitz et al. 1999) and mediates its monoubiquitination, which results in receptor endocytosis followed by endosomal/lysosomal sorting (Grøvdal et al. 2004; Haglund and Dikic 2012). Phosphorylation of Tyr1068 and Tyr1086 is required for the binding of growth factor receptor-bound protein 2 (GRB2) adaptor protein (Yamauchi et al. 1997; Rojas et al. 1996; Okutani et al. 1994), which is the key player in EGF-dependent Ras activation (Sebastian et al. 2006). Tyr1068 of EGF R also provides a docking site for the SH2 domain of signal transducer and activator of transcription 3 (STAT3) (Shao et al. 2003). Docking protein (Dok-R) binds EGF R phosphorylated at Tyr1086 and Tyr1148 (Jones and Dumont 1999). The phosphorylated EGF R Tyr1148 and Tyr1173 residues can recruit SHC (Okabayashi et al. 1994). Tyr1148 also binds PLCγ (Chattopadhyay et al. 1999) and VAV2 (Tamas et al. 2003) (Figure 1).
Fig. 1. Schematic representation of the major EGF R tyrosine phosphorylation sites. The phosphorylated receptor recruits adaptor proteins that transmit the activation signal from the receptor to different signaling pathways.
Although the major tyrosine sites of the EGF R are autophosphorylated, some are phosphorylated by intracellular tyrosine kinases (Sebastian et al. 2006). As an example, EGF R Tyr845 is phosphorylated by the proto-oncogene tyrosine-protein kinase (SRC) (Sato et al. 1995). This phosphorylation is required for EGF-induced signal transduction and activation of transcription factor 5B (STAT5b) in breast cancer cell models (Kloth et al. 2003), and mediation of EGF R binding to the mitochondrial protein cytochrome c oxidase subunit II (CoxII) (Boerner et al. 2004).
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References
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