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Epidermal growth factors and cancer

By C. Hooper *

EGFR interactions, roles and cancer therapy options by Dr. Claudie Hooper (KCL)
Contents:
1. Introduction to the epidermal growth factor receptor family
2. The RAS/ERK pathway
3. PI3 kinase/AKT pathway
4. JAK/STAT pathway
5. EGFR family and cancer
6. EGF signaling as a target for therapy
7. References

1. Introduction to the epidermal growth factor receptor family

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-D 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.

EGF signaling pathways

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
signalling 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.
These pathways act in a coordinated manner to promote cell survival.

2. The RAS/ERK pathway

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.

3. PI3 kinase/AKT pathway

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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-4E binding protein (4E-BP1) (Asnaghi et al., 2004). Collectively, these processes all promote cell growth and survival in response to EGF.

4. JAK/STAT pathway
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

5. EGFR family and cancer

There are various alterations that affect ErbB receptors in human cancers (Nair 2005; Henson and Gibson 2006). In approximately 25 % of breast cancer ErbB2 expression is
increased. ErbB2 over-expression is also associated with ovarian, gastric and bladder cancers. In glioblastoma multiforme tumors ErbB1 is often mutated in the intracellular
domain rendering the tyrosine kinase constitutively active. Furthermore, some tumors increase the production of EGF-related growth factors leading to the persistent activation of
ErbB receptors.

Viruses also exploit the EGF signaling cascade in a multitude of ways (Yarden 2001). Hepatitis B virus and Epstein-Barr virus both activate EGF receptor expression during
invasion. The avian erythoblastosis virus encodes a truncated constitutively active form of the EGF receptor, whilst the human papilloma virus E5 appears to block the degradation
of activated receptors resulting in the internalized receptor being returned to the plasma membrane.

6. EGF signaling as a target for therapy

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.

7. References
• Asnaghi L., Bruno P., Priulla M., Nicolin A. (2004) mTOR: a protein kinase switching between life and death. Pharmacol. Res. 50, 545-549.
• Henson E. S., Gibson S. B. (2006) Surviving cell death through epidermal growth factor signal transduction pathways: Implications for cancer therapy. Cell Sig. Epub ahead of
print.
• Jorrissen R. N., Walker F., Pouliot N., Garrett T. P. J., Ward C. W., Burgess A. W. (2003) Epidermal growth factor receptor: mechanisms of activation and signalling. Exp. Cell
Res. 284, 31-53.
• Kisseleva T., Bhattacharya S., Braunstein J., Schindler C. W. (2002) Signalling through the JAK/STAT pathway, recent advances and future challenges. Gene. 285, 1-24.
• Lizcano J. M. Alessi D. R. (2002) The insulin signalling pathway. Curr Biol. 12, 236-238.
• Nair P. (2005) Epidermal growth factor receptor family and its role in cancer progression. Curr. Sci. 88, 890-898.
• Yarden Y. (2001) The EGFR family and its ligands in human cancer: signalling mechanisms and the therapeutic opportunities. Eur. J. Cancer. 37, S3-S8.

Department of Neuroscience, Institute of Psychiatry, Kings College London, Denmark Hill, London, SE5 8AF. E-mail: c.hooper@iop.kcl.ac.uk

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