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by Claudie Hooper, PhD
The epidermal growth factor receptor (EGFR) family plays an important role in cell lineage determination, the morphogenesis of many organs and in cell survival in the adult (Yarden 2001; Jorrissen et al., 2003; Nair 2005; Henson and Gibson 2006). Moreover, activating mutants and over-expression of these family members contribute to oncogenesis by inducing cells to proliferate and to resist apoptosis. The EGFR family of receptor tyrosine kinases comprises the EGFR (ErbB1), ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4. ErbB2 cannot bind ligands, whereas ErbB3 has an inactive kinase domain, therefore these receptors are thought to serve as co-receptors. Ligands for the ErbB family include EGF, amphiregulin (AR) and TGF-which preferentially bind to EGFR, while betacellulin (BTC), heparin-binding EGF (HB–EGF) and epiregulin (EPR) bind to the EGFR as well as ErbB4. Neuregulins 1 (NGR1) and 2 (NGR2) bind preferentially to ErbB3 and ErbB4, whereas NGR3 and NGR4 bind to ErbB4.
Upon ligand-binding receptors homo-dimerise or hetero-dimerise triggering tyrosine trans-phosphorylation of the receptor sub-units. Intracellular tyrosine kinases of the Src family and Abl family are also able to tyrosine phosphorylate ErbB receptors. These tyrosine phosphorylated sites allow proteins to bind through their Src homology 2 (SH2) domains leading to the activation of downstream signaling cascades including the RAS/extracellular signal regulated kinase (ERK) pathway, the phosphatidylinositol 3-kinase (PI3) pathway and the Janus kinase/Signal transducer and activator of transcription (JAK/ STAT) pathway (Figure 1). Differences in the C-terminal domains of the ErbB receptors govern the exact second messenger cascades that are elicited conferring signaling specificity. The EGF signal is terminated primarily through endocytosis of the receptor-ligand complex. The contents of the endosomes are then either degraded or recycled to the cell surface.
Figure 1. Overview of the EGF signaling pathway.
Activation of the EGF receptor results in autophosphorylation of key tyrosine residues. These tyrosine phosphorylated sites allow proteins to bind through their Src homology 2 (SH2) domains and leads to the activation of downstream signaling cascades including the RAS/extracellular signal regulated kinase (ERK) pathway, the phosphatidylinositol 3-kinase (PI3K) pathway and the Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathway. These pathways act in a coordinated manner to promote cell survival.
EGF activates the ERK pathway through the binding of Grb2 or Shc to phosphorylated ErbB receptors, which in turn results in the recruitment of the son of sevenless (SOS) to the activated receptor dimer (Henson and Gibson 2006). SOS then activates RAS leading to the activation of RAF-1. RAF-1 subsequently phosphorylates MEK1 and MEK2 which activate respectively ERK1 and ERK2. This pathway results in cell proliferation and in the increased transcription of Bcl-2 family members and inhibitor of apoptosis proteins (IAPs), thereby promoting cell survival.
EGF also promotes cell survival through the activation of PI3 kinase/AKT signaling (Henson and Gibson 2006). EGF triggers the recruitment of PI3 kinase to activated ErbB receptors, which is mediated by the binding of SH2 domains in PI3 kinase to phosphorylated tyrosine residues. The catalytic subunit of PI 3-kinase in turn phosphorylates phosphatidylinositol (4,5) bisphosphate (PtdIns(4,5)P2) leading to the formation of PtdIns(3,4,5)P3. PI 3-kinase can also activate RAS, resulting in the activation of ERK signaling, thereby facilitating cross-talk between survival pathways. A key downstream effector of PtdIns(3,4,5)P3 is AKT (PKB). AKT promotes cell survival through the transcription of anti-apoptotic proteins. Intermediate transcription factors involved in this process are NFkB and CREB. Another downstream target of AKT is glycogen synthase kinase 3 (GSK3). Under basal conditions the constitutive activity of GSK3 leads to the phosphorylation and inhibition of a guanine nucleotide exchange factor eIF2B, which regulates the initiation of protein translation. Therefore, upon inactivation of GSK3 by AKT, eIF2B is dephosphorylated resulting in the promotion of protein synthesis and the storage of amino acids (Lizcano and Alessi 2002). AKT also activates mammalian target of rapamycin (mTOR), which promotes protein synthesis through p70 ribosomal S6 kinase (p70s6k) and inhibition of eIF-4Ebinding protein (4E-BP1) (Asnaghi et al., 2004). Collectively, these processes all promote cell growth and survival in response to EGF.
Another signaling cascade initiated by EGF is the JAK/STAT pathway, which is also implicated in cell survival responses (Kisseleva et al., 2002; Henson and Gibson 2006). JAK phosphorylates STAT proteins localized at the plasma membrane. This leads to the translocation of STAT proteins to the nucleus where they activate the transcription of genes associated with cell survival.
Therapies used for the treatment of EGF fuelled cancers include suramin, which inhibits the binding of EGF to its receptor and gefitinib, which targets ErbB1 tyrosine kinase activity consequently preventing autophosphorylation (Nair 2005; Henson and Gibson 2006). Other therapeutic agents include herceptin, a monoclonal antibody that targets the ErbB2 receptor and triggers receptor internalization, thereby inhibiting signaling. Similarly, cetuximab is a monoclonal antibody that prevents ErbB1 signaling by binding to the ligand binding and receptor dimerisation domains. Further understanding of EGF signaling will no doubt improve our understanding of oncogenesis and possibly provide novel targets for therapeutic intervention.