EGFR Pathway


Epidermal growth factor receptor (EGFR) is the first discovered and prototypical member of receptor tyrosine kinase family (RTK) of receptors. It is activated by various ligands in extracellular milieu and transmits the cellular response to mediate various cellular activities, including cell proliferation, cell survival, growth and development. EGFR is expressed in many organs and aberrant expression is implicated in various cancers. This review highlights various signaling components of EGFR pathway and their signal transduction pathways.

EGF Receptors and Ligands

The ErbB family comprises of four receptors, which include EGFR (ErbB-1/HER1), ErbB-2 (Neu, HER2), ErbB-3 (HER3) and ErbB-4 (HER4). This receptor tyrosine kinase family (RTK) of proteins has an extracellular ligand-binding domain, hydrophobic transmembrane domain and a cytoplasmic tyrosine kinase domain. ErbB receptors are activated by growth factors of EGF-family characterized by three disulphide-bonds that confer binding specificity. Additional structural motifs include immunoglobulin-like domains, heparin-binding sites and glycosylation sites1,2. EGFR ligands and their specific receptors are given in Table 1.

Table 1. EGFR Receptors and Ligands

Receptor Ligands
EGFR EGF, Transforming growth factor-α (TGF-α), Amphiregulin (AR), Betacellulin (BTC), Heparin-binding epidermal growth factor (HB-EGF) and Epiregulin (EPR)
ErbB2 None
ErbB3 NRG-1 and NRG-2
ErbB4 Betacellulin (BTC), Heparin-binding EGF-like growth factor (HB-EGF), Epiregulin (EPR), Tomoregulin, NRG-1, NRG2, NRG3 and NRG4

Receptor Activation

Receptor activation is triggered by the cascade of events on cell membrane.

  • Ligand binding: Each ligand binds to the extracellular domain of cognate ErbB receptors
  • Receptor dimerization: Ligand binding induces the formation of receptor homo or hetero dimers3.
  • Activation of kinase domain: Autophosphorylation of key tyrosine residues within carboxy terminal tail activates  the receptor and acts as docking sites for proteins with Src homology 2 (SH2) and phosphotyrosine binding domain (PTB) to trigger cellular signaling3,4.

EGFR Signaling

EGFR Signaling


Ras/Raf Signaling Cascade

Receptors: Dimerization of any two ErbB receptors

Key functions: Cell survival and cell proliferation5

After receptor activation, the complex formed by Grb2 and Sos binds directly or through association of adapter protein Shc, to specific tyrosine residues on the receptor6,7. This leads to conformational change in Sos, which can recruit and activate Ras-GDP. Ras-GDP activates Raf-1, which further activates extracellular regulated kinases 1 and 2 (ERK1 and ERK2) mediated through mitogen-activated protein kinases (MAPK) 8,9. Activated kinases eventually move into the nucleus to phosphorylate specific transcription factors like Elk1 and C-myc to induce cell proliferation.

Phosphatidylinositol 3-kinase/Akt Signaling Cascade

Receptors: Dimerization of ErbB2 with either ErbB4 or ErbB3

Key functions: Cell growth, apoptosis resistance, cell invasion and migration10

Phosphatidylinositol comprises of p85 and p110 sub units that dock to the ErbB receptor to generate secondary messenger phosphatidylinositol 3,4,5-triphosphate, that further activates serine/threonine kinase AKT. Upon activation, AKT phosphorylates mTOR and subsequently S6K which mediates protein synthesis10.

Signal Transducers and Activators of Transcription (STAT) Pathway

Receptors: ErbB

Key functions:
Tumor progression, oncogenesis and angiogenesis11

STAT proteins docks to the phosphotyrosine residues of ErbB receptors via Src homology 2 domains and up on dimerization, translocate into the nucleus to promote the expression of specific target genes like Myc, Nos2, p21 and cytokines12.

Phospholipase Cγ Signaling

Receptors: ErbB1

Key functions: Regulation of ion channels, cell migration, calcium-mediated signaling13

Phospholipase Cγ interacts with ErbB1 and hydrolyses phosphatidylinositol 4,5-diphosphate (PIP2) to generate inositol 1,3,5-triphosphate (IP3) and 1,2 diacylglycerol (DAG). IP3 increases intracellular calcium levels and DAG mediates activation of protein kinase C (PKC)13. Activated PKC in turn activates MAPK and c-Jun NH2-terminal kinase14.

Nck/PAK Signaling Cascade

Receptors: ErbB1

Key functions: Cell survival and cell migration15

Nck is an adaptor protein containing SH2 domain that binds to EGF receptor and triggers downstream signaling. Nck activates PAK1 (p21/CDC42/Rac1-Activated Kinase-1) binding through SH3 domain. Activated PAK1 in turn activates JNKs (c-Jun Kinases) mediated by MEKK1 (MAP/ERK Kinase Kinase-1) and MKK4/7 (MAP Kinase Kinase-4/7), respectively. JNK translocates to the nucleus and phosphorylates transcription factors like c-Fos and c-Jun16.

Cbl mediated Endocytosis

Receptors: ErbB1

Key functions: Endocytosis

Following ligand binding, Cbl is a substrate that binds to the EGF receptors through SH2 domains or through GRB2 adaptor protein and triggers lysosomal degradation of receptors17.


EGFR Translocation Into Nucleus

EGF Receptors have an ability to escape lysosomal degradation and translocate into the nucleus to mediate biological functions. In the nucleus, these receptors promote transcription of cell survival genes like Cyclin D1 gene and also act as cofactors for STAT and E2F1 transcription factors18.  Nuclear localization of EGFR is implicated in disease severity by conferring resistance to growth inhibitory effects of anti-cancer mAbs19.

EGF Receptors in Development

EGFR signaling is important for development of various organs; EGFR knockout models show embryonic lethality and defective tissues/organs. However, mutations in ErbB ligands do not show any lethal phenotype, because the complimentary pathways of other ligands compensate the abrogated signals of mutated ErbB ligand.

Table 2. Mutation of ErbB Receptors Produces Abnormal Phenotypes, Which Result in Embryonic Death

Mutation of receptors Phenotype
ErbB1 Defects in skin, lung, pancreas, central nervous system, gastrointestinal tract and ductal morphogenesis in mammary gland20,21
ErbB2 Arrest in Myelin formation, oligodendrocyte development and defects in  cardiac, neural structures and milk secretion22,23
ErbB3 Defects in neural cells and altered cardiac valve formation24
ErbB4 Abnormalities in behavioral and motor activities and milk secretion25

EGF Receptors in Human Disorders

EGF receptors and their ligands are abnormally activated or expressed in many diseases. Specifically, their role in cancer progression is well investigated. Some of genetic alterations and their phenotypic effects are summarized in Table 3.

Table 3. Genetic Alterations of EGFR Receptors in Human Disorders

Genetic Alteration Implication
Mutation in EGFR T790M Non-small cell lung cancer26
Mutation in EGFR S492R Resistance towards cetuximab in colorectal cancer27
L858R mutation and deletion of exon 19 in EGFR Non-small-cell lung cancer28
Copy number gain of EGFR Anaplastic thyroid cancer and follicular thyroid cancer29
EGFR mutation Lung adenocarcinomas30
Increase expression ErbB2 Gastric and breast cancer31,32
Increase expression of ErbB2 and ErbB3 Prostate cancer33
Dysregulated EGFR signaling Polycystic kidney disease, rapidly progressive glomerulonephritis and diabetic nephropathy34
Overexpression of EGFR Enhance generation of new oligodendrocytes . Potential in treatment of white matter injury in pre-mature children35
Mutation in EGFR G428D Inflammatory skin and bowel disease36

EGFR Inhibitors

Currently, EGFR inhibitors are used to treat cancers exclusively, of them small molecules inhibit EGFR tyrosine kinase activity while monoclonal antibodies bind to the extracellular domain and competitively inhibit ligand binding. Drugs that are approved and are in market are given in Table 4.

Table 4. Approved Drugs Targeting EGFR Receptors

Drug Drug Type Target Indication
Afatinib Small molecule ErbB1, ErbB2 and ErbB4 Non-small cell lung cancer
Erlotinib Small molecule ErbB1 Non-small cell lung cancer
Gefitinib Small molecule ErbB1 Non-small cell lung cancer
Lapatinib Small molecule ErbB1, ErbB2 Breast cancer and gastric cancer
Nimotuzumab mAbs ErbB1 Glioma, nasopharyngeal cancer and, head and neck cancer
Cetuximab mAB ErbB1 Colorectal cancer


EGFR signaling has pleiotropic functions in development and regulates various physiological functions. The aberrant expression of EGF receptors has been increasingly implicated in various disorders. Since, the discovery of biological effects of EGFR signaling, efforts were made to discover drugs, that inhibit tyrosine kinase activity and many of them are approved for various cancers. However, some clinical patients have intrinsic resistance and others develop acquired resistance to the drugs due to the mutation of kras/MEK1 and PIK3 kinase genes. In addition, compensatory cross talk among different receptors within the signaling network also adds to the complexity of drug resistance. More research is yet to clearly uncover the role of EGFR signaling in development of various organs including, brain, heart, skin, kidneys, mammary glands and lungs. Efforts to identify novel drugs with high efficacy, sustained drug activity and less cross reactivity to combat drug-resistant cancer conditions continue to pique lot of research interest.

Explore complete offering of high quality EGF recombinant proteins and receptors for your research use here.

Study EGF signaling with consistency in your stem cell cultures. Visit our Stem Cell Learning Center to learn more.

View our complete offering of Growth Factors and Cytokines.



  1. Arteaga, C. L., and Engelman, J. A. (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25, 282–303.
  2. Kovacs, E., Zorn, J. A., Huang, Y., Barros, T., and Kuriyan, J. (2015) A structural perspective on the regulation of the epidermal growth factor receptor. Annu. Rev. Biochem. 84, 739–764.
  3. Capuani, F., Conte, A., Argenzio, E., Marchetti, L., Priami, C., Polo, S., Di Fiore, P. P., Sigismund, S., and Ciliberto, A. (2015) Quantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells. Nat. Commun. 6, 7999.
  4. Zhang, X., Gureasko, J., Shen, K., Cole, P. A., and Kuriyan, J. (2006) An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125, 1137–1149.
  5. Gaestel, M. (2006) MAPKAP kinases - MKs - two’s company, three’s a crowd. Nat. Rev. Mol. Cell Biol. 7, 120–130.
  6. Lowenstein, E. J., Daly, R. J., Batzer, A. G., Li, W., Margolis, B., Lammers, R., Ullrich, A., Skolnik, E. Y., Bar-Sagi, D., and Schlessinger, J. (1992) The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 70, 431–442.
  7. Batzer, A. G., Rotin, D., Ureña, J. M., Skolnik, E. Y., and Schlessinger, J. (1994) Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Mol. Cell. Biol. 14, 5192–5201.
  8. Hallberg, B., Rayter, S. I., and Downward, J. (1994) Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation. J. Biol. Chem. 269, 3913–3916.
  9. Liebmann, C. (2001) Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity. Cell. Signal. 13, 777–785.
  10. Vivanco, I., and Sawyers, C. L. (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501.
  11. Niu, G., Wright, K. L., Huang, M., Song, L., Haura, E., Turkson, J., Zhang, S., Wang, T., Sinibaldi, D., Coppola, D., Heller, R., Ellis, L. M., Karras, J., Bromberg, J., Pardoll, D., Jove, R., and Yu, H. (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21, 2000–2008.
  12. Bromberg, J. (2002) Stat proteins and oncogenesis. J. Clin. Invest. 109, 1139–1142.
  13. Patterson, R. L., van Rossum, D. B., Nikolaidis, N., Gill, D. L., and Snyder, S. H. (2005) Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling. Trends Biochem. Sci. 30, 688–697.
  14. Schönwasser, D. C., Marais, R. M., Marshall, C. J., and Parker, P. J. (1998) Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol. Cell. Biol. 18, 790–798.
  15. Ye, D. Z., and Field, J. (2012) PAK signaling in cancer. Cell. Logist. 2, 105–116.
  16. Tomar, A., and Schlaepfer, D. D. (2010) A PAK-activated linker for EGFR and FAK. Dev. Cell 18, 170–172.
  17. Yu, P., Fan, Y., Qu, X., Zhang, J., Song, N., Liu, J., and Liu, Y. (2016) Cbl-b regulates the sensitivity of cetuximab through ubiquitin-proteasome system in human gastric cancer cells. J. BUON Off. J. Balk. Union Oncol. 21, 867–873.
  18. Lo, H.-W., Hsu, S.-C., Ali-Seyed, M., Gunduz, M., Xia, W., Wei, Y., Bartholomeusz, G., Shih, J.-Y., and Hung, M.-C. (2005) Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell 7, 575–589.
  19. Lo, H.-W., Xia, W., Wei, Y., Ali-Seyed, M., Huang, S.-F., and Hung, M.-C. (2005) Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer. Cancer Res. 65, 338–348.
  20. Miettinen, P. J., Berger, J. E., Meneses, J., Phung, Y., Pedersen, R. A., Werb, Z., and Derynck, R. (1995) Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337–341.
  21. Sibilia, M., and Wagner, E. F. (1995) Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–238.
  22. Park, S. K., Miller, R., Krane, I., and Vartanian, T. (2001) The erbB2 gene is required for the development of terminally differentiated spinal cord oligodendrocytes. J. Cell Biol. 154, 1245–1258.
  23. Leu, M., Bellmunt, E., Schwander, M., Fariñas, I., Brenner, H. R., and Müller, U. (2003) Erbb2 regulates neuromuscular synapse formation and is essential for muscle spindle development. Dev. Camb. Engl. 130, 2291–2301.
  24. Erickson, S. L., O’Shea, K. S., Ghaboosi, N., Loverro, L., Frantz, G., Bauer, M., Lu, L. H., and Moore, M. W. (1997) ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2-and heregulin-deficient mice. Dev. Camb. Engl. 124, 4999–5011.
  25. Golub, M. S., Germann, S. L., and Lloyd, K. C. K. (2004) Behavioral characteristics of a nervous system-specific erbB4 knock-out mouse. Behav. Brain Res. 153, 159–170.
  26. Maheswaran, S., Sequist, L. V., Nagrath, S., Ulkus, L., Brannigan, B., Collura, C. V., Inserra, E., Diederichs, S., Iafrate, A. J., Bell, D. W., Digumarthy, S., Muzikansky, A., Irimia, D., Settleman, J., Tompkins, R. G., Lynch, T. J., Toner, M., and Haber, D. A. (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med. 359, 366–377.
  27. Montagut, C., Dalmases, A., Bellosillo, B., Crespo, M., Pairet, S., Iglesias, M., Salido, M., Gallen, M., Marsters, S., Tsai, S. P., Minoche, A., Seshagiri, S., Somasekar, S., Serrano, S., Himmelbauer, H., Bellmunt, J., Rovira, A., Settleman, J., Bosch, F., and Albanell, J. (2012) Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat. Med. 18, 221–223.
  28. Rosell, R., Moran, T., Queralt, C., Porta, R., Cardenal, F., Camps, C., Majem, M., Lopez-Vivanco, G., Isla, D., Provencio, M., Insa, A., Massuti, B., Gonzalez-Larriba, J. L., Paz-Ares, L., Bover, I., Garcia-Campelo, R., Moreno, M. A., Catot, S., Rolfo, C., Reguart, N., Palmero, R., Sánchez, J. M., Bastus, R., Mayo, C., Bertran-Alamillo, J., Molina, M. A., Sanchez, J. J., Taron, M., and Spanish Lung Cancer Group. (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med. 361, 958–967.
  29. Liu, Z., Hou, P., Ji, M., Guan, H., Studeman, K., Jensen, K., Vasko, V., El-Naggar, A. K., and Xing, M. (2008) Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J. Clin. Endocrinol. Metab. 93, 3106–3116.
  30. Gao, S. P., Mark, K. G., Leslie, K., Pao, W., Motoi, N., Gerald, W. L., Travis, W. D., Bornmann, W., Veach, D., Clarkson, B., and Bromberg, J. F. (2007) Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J. Clin. Invest. 117, 3846–3856.
  31. Fukushige, S., Murotsu, T., and Matsubara, K. (1986) Chromosomal assignment of human genes for gastrin, thyrotropin (TSH)-beta subunit and C-erbB-2 by chromosome sorting combined with velocity sedimentation and Southern hybridization. Biochem. Biophys. Res. Commun. 134, 477–483.
  32. Slamon, D. J., Godolphin, W., Jones, L. A., Holt, J. A., Wong, S. G., Keith, D. E., Levin, W. J., Stuart, S. G., Udove, J., and Ullrich, A. (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707–712.
  33. Qiu, Y., Ravi, L., and Kung, H. J. (1998) Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nature 393, 83–85.
  34. Harskamp, L. R., Gansevoort, R. T., van Goor, H., and Meijer, E. (2016) The epidermal growth factor receptor pathway in chronic kidney diseases. Nat. Rev. Nephrol. 12, 496–506.
  35. Scafidi, J., Hammond, T. R., Scafidi, S., Ritter, J., Jablonska, B., Roncal, M., Szigeti-Buck, K., Coman, D., Huang, Y., McCarter, R. J., Hyder, F., Horvath, T. L., and Gallo, V. (2014) Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature 506, 230–234.
  36. Campbell, P., Morton, P. E., Takeichi, T., Salam, A., Roberts, N., Proudfoot, L. E., Mellerio, J. E., Aminu, K., Wellington, C., Patil, S. N., Akiyama, M., Liu, L., McMillan, J. R., Aristodemou, S., Ishida-Yamamoto, A., Abdul-Wahab, A., Petrof, G., Fong, K., Harnchoowong, S., Stone, K. L., Harper, J. I., McLean, W. H. I., Simpson, M. A., Parsons, M., and McGrath, J. A. (2014) Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR. J. Invest. Dermatol. 134, 2570–2578.