Epidermal growth factor receptor (EGFR) also known as ErbB1/HER1 is a member of the ErbB family of receptor tyrosine kinases which also includes ErbB2 (Neu, HER2), ErbB3 (HER3) and ErbB4 (HER4). Several ligands such as epidermal growth factor, transforming growth factor-alpha, epigen, amphiregulin, betacellulin, heparin-binding EGF and epiregulin are known to specifically bind to EGFR (1,2). Epidermal growth factor (EGF) is one of the high affinity ligands of EGFR. EGF/EGFR system induces growth, differentiation, migration, adhesion and cell survival through various inter-acting signaling pathways (3,4,5,6,7,8,9).
The binding of EGF to the extracellular domain of EGFR induces the dimerization, activation of intrinsic kinase activity and subsequent autophosphorylation of EGFR at multiple residues in the cytoplasmic region such as Tyr 1092, Tyr 1172, Tyr 1197, Tyr 1110, Tyr 1016) (10,11,12). Activated EGFR recruits various cytoplasmic proteins which transduce and regulate the EGFR function. The proteins recruited to active EGFR include many Src homology 2 (SH2) and phosphotyrosine binding (PTB) domain containing proteins which binds to the tyrosine phosphorylated residues in EGFR, enzymes which act on EGFR and also various EGFR substrates(13,14,15,16,17,18,19,20,21).
One of the adapter proteins, GRB2, binds to the phosphotyrosine residue at 1068 and recruits SOS to the membrane (22). SOS activates GDP/GTP exchange which recruits RAF to the membrane. RAF phosphorylates MEKs, which then activates the extracellular signal regulated kinase (ERK) (23,24). ERK activates a number of transcriptional regulators to induce cell growth and proliferation. GRB2 or other adaptor proteins such as GABs recruits PI3Ks, another major mediator of EGFR signaling. PI3Ks convert Phosphatidylinositol-4,5-bisphosphate (PIP2) to Phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 binds to PH domain of AKT and recruits it to plasma membrane (25,26). PDK1 phosphorylates AKT which in turn regulate the activity of various proteins that mediate cell survival (27). EGFR also activate phospholipase C which hydrolyses PIP2 to generate Inositol trisphosphate (IP3) and 1,2-Diacylglycerol (DAG). IP3 induces the release of Ca2+ from endoplasmic reticulum to activate calcium regulated pathways. DAG activates protein kinase C pathway (28). One of the signaling modules regulated by PKC in EGFR pathway is the NFKB module (29). The protein SRC is a key player in the activation of various pathways such as RAS, PLC and also the STAT proteins in various cells (30,31,32). Other signaling modules activated by EGFR include the FAK, JNK, p38MAPK and ERK5 modules. EGFR induces the JNK pathway through the activation of G proteins such as RAC and CDC42 which recruits JNK kinases as well as regulate the actin polymerization (33). EGFR also translocates from the plasma membrane to other cellular compartments including nucleus where it directly regulate the expression of several genes in cooperation with other transcriptional regulators such as STATs, PCNA and E2F family of proteins(34).
Being a growth, differentiation and cell survival factor; mutations and overexpression of EGFR and also the defective regulation of its signal transduction pathways has been established to be associated with oncogenesis (35). Thus, EGFR and its signaling components are promising targets for effective therapy for various cancers. There are several proteins which have been reported to regulate the EGFR signaling such as CBL, CSK, PKC and PTEN which promotes endocytosis or reduction in the EGFR activity or its signaling mediators(36,37,38,39). The major endocytic pathway of EGFR is established to be the clathrin coated pits which delivers them to endosomes. The endosomal pathway recycles the membraneous form of EGFR or form multivesicular bodies (MVB) and fuse with lysosomes for to the degradation pathway (40,41,42).
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