Figure 1. EGF/EGFR Signaling Pathway.
EGFR(Epidermal growth factor receptor), or ErbB1/human epidermal growth factor receptor (HER)-1, is a transmembrane protein which is the receptor of the ligands from EGF family. EGFR is a 170-kDa glycoprotein with tyrosine kinase activity. It is composed of a single polypeptide of 1186 amino acid residues that is cleaved from a 1210-residue polypeptide precursor. It has its own modular structure: it contains an extracellular ligand-binding domain, a transmembrane region and a cytoplasmic tyrosine-kinase region that is flanked by noncatalytic regulatory regions. EGFR plays a crucial role in initiating the signaling that directs the behavior of epithelial cells and tumors of epithelial origin. Human EGF is a 53-aa polypeptide, whose molecular weight is 6KDa. EGF can stimulate the cell growth and differentiation by binding to its receptor, EGFR.
EGF/EGFR signaling pathway
EGF/EGFR signaling pathway cascade
EGFR signaling pathway is one of the most important pathways in mammalian cells, which regulate a series of important events including proliferation, migration, differentiation, apoptosis, as well as those that regulate intercellular communication during development. Mutation in the certain component in this pathway will cause human cancer. So it has been considered as an ideal therapeutic target.
Signaling proteins which have src homology-2(SH2) or phosphotyrosine binding(PTB) domains can bind to the EGFR family members after tyrosine phosphorylation. One of these signaling proteins is p52 SH2 domain containing α2 collagen related protein(Shc), which is an adaptor protein. Both the amino terminal SH2 domain and the carboxy terminal PTB domain of Shc can be used to bind to the tyrosine phosphorylated EGFR family members. Shc also becomes tyrosine phosphorylated after binding to the EGFR. And then another adaptor protein comes in called growth factor receptor binding protein-2(Grb2) which can bind to the tyrosine phosphorylated Shc as well as the tyrosine phosphorylated EGFR family members. Besides the SH2 domain, Grb2 also has two src homology-3(SH3) domains which can bind to the proline rich PXXP motifs. They are responsible for the constitute relation of Grb2 with carboxy terminal PXXP motifs present in Sos-1, which is the member of the sonof sevenless (Sos) family of guanine nucleotide exchange factors(GEFs). Recruitment of Sos-1 to the activated EGFR makes it into close proximity with the members of p21 Ras family of guanine nucleotide binding proteins. Isoforms of p21 Ras family are activated by binding to GTP rather than GDP. So they can be activated by the Sos-1 because it has the ability to exchange GDP bound to the p21 Ras family members with GTP. Subsequently, activated p21 Ras family members activate the members of Raf family of Kinase, which consists of A-Raf, B-Raf and Raf-1. Then the Raf family members will activate the mitogen activated extracellular signal regulated kinase(ERK) activating kinase(MEK) family, which includes MEK1 and MEK2, through phosphorylating regulatory residues of these kinases. ERK family members will be activated by the MEK family members by the similar mechanism.
The well-established traditional function of EGFR is known to transmit extra-cellular mitogenic signals, such as EGF and transforming growth factor-α (TGF-α), through activating a number of downstream signaling cascades. These include signaling modules that involve phospholipase C-γ, Ras, and phosphatidylinositol-3 kinase (PI-3K). In cancer cells, the common outcomes following the activation of the EGFR-mediated downstream pathways are altered gene activities, leading to un-controlled tumor proliferation and apoptosis.
Positive feedback enhances the amplitude and prolong the active state of the signaling pathway. In case of EGFR signaling pathway, ERBB2 can be regarded as an important positive regulator, which functions as the preferred secondary receptor. In addition, heterodimers containing ERBB2 evade negative regulation. Another crucial mechanism of positive regulation is that EGF-like ligands are produced after the receptor activation. For example, EGFR-mediated activation of the Ras-MAPK pathway strongly induces the transcription of some ERBB ligands, such as TGFα and HB-EGF.
Firstly, some attenuators have existed, like density-enhanced phosphatase-1 (DEP1) which dephosphorylates EGFR and protein tyrosine phosphatase-1B (PTP1B) which dephosphorylates PTKs. On the other site, some newly attenuators will be synthesized newly after the stimulation. For example, EGF treatment can induce the expression of cytokine signalling-5 (SOCS5) which results in a remarkable reduction in the level of the receptor by promoting the degradation of EGFR.
Relationship with diseases
EGFR family members have been discovered to be involved in a wide range of human diseases from psoriasis, cancer, inflammation, heart diseases and Alzheimer’s disease. Almost all the carcinomas express significant levels of EGFR. These receptors are related to the maintenance of the transformed state in these carncinomas. EGFR is remarkably over expressed in glioblastoma and as for a large number of these cancers, EGFR is truncated and consequentialy activated. Notably, at present, major clinical trials have been directed against blocking EGFR and erbB2 signaling in tumors.
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