Epidermal Growth Factor Receptor (EGF R)

Epidermal Growth Factor Receptor (EGF R)

The most studied receptor tyrosine kinase

The epidermal growth factor receptor (EGF R), also known ERBB1 or HER1, is the most extensively studied receptor tyrosine kinase with approximately 70,000 publications. However, such is the complexity of its behaviour that it still requires further investigation. EGF R is one of four members of a family of receptors. The other members of this family are ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4.

Receptor

Features

EGFR/ERBB1/HER1

Forms heterodimers with several non ERBB members

ERBB2/HER2

No known ligand, freely forms heterodimers

ERBB3/HER3

Lacks active kinase domain, ligands include Heregulin and Neuregulin

ERBB4/HER4

Ligands include Heregulin and Neuregulin

EGF R is a transmembrane receptor consisting of a large extracellular region, a single transmembrane domain and an intracellular region. The extracellular region is approximately 620 amino acids in length and can be subdivided into four domains. Domains 1 and 3 are responsible for ligand binding while domain 2 and 4 are involved in receptor dimerization. The intracellular section of EGF R contains a kinase domain and a cytoplasmic tail. EGF R, when produced at the ribosome, is 1,210 amino acids in length and undergoes cleavage of the first 24 amino acids reducing its length to 1,186 amino acids. Numbering of amino acid residues is most often based on the cleaved protein however some organisations use the full protein when numbering amino acids.

EGF R Ligands

Seven ligands, listed in Table 1, bind to and activate EGF R. The seven ligands are epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), heparin-binding EGF-like growth factor (HB-EGF), betacellulin, amphiregulin, epiregulin and epigen (Singh et al. 2016). All EGF R ligands are produced in a precursor transmembrane form which undergoes cleavage to release the extracellular soluble ligand. This cleavage is typically performed by members of the ADAM family of proteases. Once in the extracellular space, the EGF R ligands are free to bind to the available receptors. Ligand binding causes a conformational change in the four extracellular domains of EGF R and leads to dimerization of the receptor as shown simplistically in Figure 1. Dimerization of the extracellular domains brings the kinase domains of the two receptors closer allowing interaction between them. They then become allosterically activated following formation of the asymmetric dimer. For more detailed information on receptor dimerization see Kennedy et al. (2016) and Lemmon et al. (2014).

Fig. 1. Ligand binding induces receptor dimerization.


Fig. 1. Ligand binding induces receptor dimerization. Dimerization results in significant rearrangement of the extracellular domains as well as an interaction between the cytoplasmic domains leading to kinase activation.

Table 1. EGF R ligands, affinity for EGF R and other receptors for the EGF R ligands.

 

Affinity for EGF R

Other Receptors

EGF

High

 

TGF-α

High

 

Amphiregulin

Low

 

Epiregulin

Low

ERBB4

Betacellulin

High

ERBB4

HB-EGF

High

ERBB4

Epigen

Low

 

Phosphorylation of EGF R and downstream signaling

EGF R activates several signaling cascades. Ligand binding induces receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues listed in Figure 2 and Table 2. The phosphorylated receptor recruits adapter proteins such as GRB2 which activate downstream signaling cascades including RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLC gamma-PKC and STAT.

Fig. 2. Phosphorylation of EGF R


Fig. 2. Phosphorylation of EGF R. Ligand binding induces the EGF R to dimerize with another receptor. This leads to allosteric activation of the kinase domain and phosphorylation of several cytoplasmic residues. Phosphorylation of these residues can activate several signaling cascades.

Table 2. Phosphorylation sites on the cytoplasmic domains of EGF R and their associated signaling pathways.

Residue

Phosphorylated by

Downstream

Y845

Activated by receptor dimerization /transphosphorylation/autophosphorylation/Src

STAT5

Y974

SRC

AP-2 mediated receptor internalisation

Y992

Autophosphorylation

PLC/PKC activation

Y1045

SRC

CBL/ubiquitination /degradation

Y1068

Autophosphorylation

GRB2/MAPK/ERK

Y1086

Autophosphorylation

PI3K/PKB/MAPK/ERK

Y1101

SRC

PI3K/PKB

Y1148

Autophosphorylation

SHC/MAPK/ERK

Y1173

Autophosphorylation

SHC/MAPK/ERK/ SHP1 receptor dephosphorylation


EGF R in cancer

Mutations in the EGF R have been associated with a number of cancers, including non-small-cell lung cancer (Sharma et al. 2007) and glioblastoma (Padfield et al. 2015). These somatic mutations involving EGF R lead to its constant activation, which produces uncontrolled cell division. The identification of EGF R as an oncogene has led to the development of therapeutic EGF R inhibitors including panitumumab, gefitinib, erlotinib, afatinib, brigatinib, icotinib and cetuximab. Cetuximab and panitumumab are examples of monoclonal antibody inhibitors. The monoclonal antibodies block the extracellular ligand binding domain. With the binding site blocked, signal molecules can no longer attach there and activate the tyrosine kinase preventing the pro-survival and proliferative effects of EGF R.


EGF Product Range


EGF R ligands

Catalog #

Product Type

Product

EGF1

Purified protein

Mouse EGF

PRP31

Recombinant protein

Recombinant Rat EGF

PHP030A

Recombinant protein

Recombinant Human EGF

PHP037

Recombinant protein

Recombinant Human TGF Alpha

EGF antibodies for western blot

Catalog #

Product Type

Product

AHP767

Polyclonal antibody

Rabbit Anti-Human EGF

AAR37

Polyclonal antibody

Rabbit Anti-Rat EGF

AAM52

Polyclonal antibody

Goat Anti-Mouse EGF

MCA5986GA

Monoclonal antibody

Mouse Anti-Human EGF Receptor

AHP1243

Polyclonal antibody

Rabbit Anti-Human EGF Receptor

AHP2586

Polyclonal antibody

Rabbit Anti-EGF R (pSer1046)

AHP2587

Polyclonal antibody

Rabbit Anti-EGF R (pThr654)

AHP2588

Polyclonal antibody

Rabbit Anti-EGF R (pThr669)

AHP2590

Polyclonal antibody

Rabbit Anti-EGF R (pTyr1068)

AHP2592

Polyclonal antibody

Rabbit Anti-EGF R (pTyr1086)

AHP2594

Polyclonal antibody

Rabbit Anti-EGF R (pTyr1148)

AHP2595

Polyclonal antibody

Rabbit Anti-EGF R (pTyr1173)

AHP2597

Polyclonal antibody

Rabbit Anti-EGF R (pTyr845)

AHP2589

Polyclonal antibody

Rabbit Anti-EGF R (pTyr992)

VMA00061K

PrecisionAb™ monoclonal

EGF Receptor Antibody with Control Lysate

VMA00061

PrecisionAb monoclonal

Mouse Anti-EGF Receptor

VMA00061KT

PrecisionAb monoclonal

Mouse Anti-EGF Receptor

EGF antibodies for IHC

Catalog #

Product Type

Product

IHC type

MCA1784

Monoclonal antibody

Rat Anti-Human EGF Receptor

IHC-F & IHC-P

AHP767

Polyclonal antibody

Rabbit Anti-Human EGF

IHC-P

AHP1372

Polyclonal antibody

Rabbit Anti-Human EGF Receptor (C-Terminal)

IHC-P

EGF antibodies for flow cytometry 

Catalog #

Product Type

Product

MCA2199

Monoclonal antibody

Sheep Anti-Human EGF Receptor

MCA2198

Monoclonal antibody

Sheep Anti-Human EGF Receptor

MCA1784F

Monoclonal antibody

Rat Anti-Human EGF Receptor:FITC

MCA1784PE

Monoclonal antibody

Rat Anti-Human EGF Receptor:RPE


References