EGFR

Epidermal growth factor receptor (EGFR), its family members Her-2/ErbB-2, Her-3, Her-4 and their ligands, are involved in over 70% of all cancers. EGFR itself has been implicated in ~30% of all solid human tumors. EGFR is associated not only with the proliferation of tumor cells, but also with enhanced tumor cell survival, angiogenesis and metastatic spread. The enhanced activity of the EGFR due to over-expression, co-expression of the receptor and its ligands, as well as activating mutations is the hallmark of many human carcinomas.

The co-expression of the EGFR and its ligands, especially TGFα and EGF, plays a key role in EGFR-mediated tumorigenesis. EGFR expression is a prognostic indicator, predicting poor survival and indicating an advanced state of the disease. When EGFR is co-expressed with other members of the Her family, the various combinations of Her dimers confer different degrees of malignancy. It has been noted that the co-expression of EGFR with Her-2 and Her-3 is associated with more aggressive clinical behavior. In many types of tumor, including lung, breast, prostate, ovary, gastrointestinal tract and brain, the EGFR receptor is expressed approximately 100 times the normal number of EGF receptors found on the surface of normal cells. Furthermore, expression of high levels of these two receptors in nonmalignant cell lines, either alone or in combination, leads to a transformed phenotype.

Due to all these observations, it is no surprise that EGFR and Her-2/Erb-2 were identified early on as important targets for drug development. Indeed, the first signal transduction therapeutic agent introduced into the clinic was Herceptin, an anti-Her-2 antibody, followed closely by the protein tyrosine kinase inhibitors Iressa (ZD 1839) and Tarceva (OSI-774) and the anti-EGFR antibody Erbitux (mAb 225).

The enhanced activity of the EGFR is due to a number of molecular events. Most common is the overexpression of the receptor along with the expression of the EGFR receptor ligands like TGFα, EGF, amphiregulin and HB-EGF, leading to persistent autocrine stimulation. Another common occurrence is an activating mutation resulting from deletion of exons 2 through 7, leading to a persistently active receptor Δ (2-7)EGFR (also known as EFFRvIII) in the absence of a ligand. The emergence of this mutation occurs in the most aggressive forms of EGFR overexpressing tumors.

Activation of the EGFR pathway is not limited to members of the EGFR family, but frequently occurs due to the transactivation by other signaling pathways such as mitogenic G protein-coupled receptors and the PDGF receptor. Furthermore, the EGFR pathway cooperates in a synergistic manner with pp60c-Src, and the deletion of PTEN, the negative regulator of PKB/Akt. The frequent involvement of EGFR in human tumors has identified it as a target for novel therapies. The first breakthrough was the development of selective EGFR kinase inhibitors (tyrphostins) like tyrphostins, AG 1478 and ZD 1839 (Iressa). Iressa is one of the two kinase inhibitors (the other being Gleevec) to receive approval for clinical application. It is important to note that it was recently found that the response of patients suffering from non-small-cell lung carcinoma to Iressa, is limited to the 7-10% harboring mutations in the kinase domain of the receptor. Other inhibitors, similar to Iressa, like Tarceva (OSI-774), the pan-Her reversible inhibitor GW 2016, the irreversible inhibitor CI-1033, which targets both RGFR and Her-2, are in the pipeline. Antibodies to the EGFR, like Erbitux and TGFα fused to a mutated form of pseudomonas exotoxin, TP-38, have also undergone clinical development.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Family Members EGFR ErbB2
Other Names ErbB-1 (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog)
HER1
ERBB
crbB
Neu (rat)
HER2
Molecular Weight ~180 kDa ~185 kDa
Structural Data 1210 aa 1255 aa
Isoforms Four alternatively spliced transcripts
Secreted extracellular domain
Auto-activating deletions in the extracellular domain
Two alternatively spliced transcripts
Secreted form (Herstatin)
Species All four receptors are expressed in mammals. A single ortholog of the receptor is expressed in D. melanogaster and C. elegans
Domain
Organization
All four receptors have similar structural domains comprising of an extracellular ligand binding domain, a single transmembrane domain, an intracellular tyrosine kinase domain and a large unstructured tail
Phosphorylation
Sites
Tyr845
Tyr891
Tyr920
Tyr974
Tyr992
Tyr1045
Tyr1068
Tyr1045
Tyr1086
Tyr1101
Tyr1114
Tyr1148
Tyr1173
Tyr654
Tyr669
Ser1046
Ser1047
Tyr882
Tyr 899
Tyr958
Tyr1023
Tyr1028
Tyr1139
Tyr1143
Tyr1196
Tyr1221/22
Tyr1226
Tyr1227
Tyr1249
Tyr1253
Tissue
Distribution
Brain, neurons, skeletal muscle, prostate, liver, pancreas, lung, tongue, skin, kidney, trachea Brain, spinal cord, placenta, prostate, heart, liver, lung, kidney, pancreas
Subcellular
Localization
Not Known
Not Known
Binding Partners/
Associated Proteins
EGF (E9644)
Neuregulin-1
Upstream
Activators
Epidermal growth factor (EGF) (E9644)
Transforming growth factor-α (TGF-α) (T7924)
Amphiregulin (AR) (A7080)
Heparin binding-EGF (HB-EGF) (SRP3052)
Betacellulin (BTC) (B3670)
Epiregulin (EPR) (E8780)
Epigen (EPG) (SRP4969)
Does not bind any of the known EGF like ligands
Downstream
Activation
Grb-2-SOS
Shc
Shp1
c-Src
Gab1
PLC-γ
PKC
c-Cbl
Grb-2-SOS
Shc
Activators Not Known
Not Known
Inhibitors Gefitinib
Erlotinib
EKB-569
GW572016
PKI-166
AEE-788
CI-1033 (C7249)
AG1478 (T4182)
TAK-165
GW572016
AEE-788
CI-1033 (C7249)
PKI-166
Selective
Activators
Not Known
Not Known
Physiological
Function
Receptor for EGF; involved in control of cell growth and differentiation Essential component of a neuregulin-receptor complex
Disease
Relevance
Glioblastoma, malignant neoplasms and carcinomas including adenocarcinomas of the breast, lung, prostate, pancreas, head and neck, colon, ovary, bladder Hyperplasias, benign and malignant, neoplasms and carcinomas, including adenocarcinomas of the breast, prostate, lung, stomach, bladder, colon, cervix

 

 

Family Members ErbB3 ErbB4
Other Names HER3 HER4
Molecular Weight ~190 kDa ~180 kDa
Structural Data 1342 aa 1308 aa
Isoforms Two alternatively spliced transcripts Two alternatively spliced transcripts called HER4 JM-α and HER4 JM-β
Species All four receptors are expressed in mammals. A single ortholog of the receptor is expressed in D. melanogaster and C. elegans
Domain
Organization
All four receptors have similar structural domains comprising of an extracellular ligand binding domain, a single transmembrane domain, an intracellular tyrosine kinase domain and a large unstructured tail
Phosphorylation
Sites
Has an impaired kinase and cannot autophosphorylate
Tyr1035
Tyr1178
Tyr1180
Tyr1203/5
Tyr1241
Tyr1243
Tyr1257
Tyr1270
Tyr1309
Tyr1066
Tyr1162
Tyr1066
Tyr1188
Tyr1189
Tyr1242
Tyr1258
Tyr1284
Tissue
Distribution
Brain, prostate, dorsal root ganglion, liver, placenta, salivary gland, spinal cord, uterus, heart, lung, muscle, pituitary, thyroid, pancreas, kidney Brain, bone marrow, spinal cord, dorsal root ganglion, testis, liver, skeletal muscle, cardiac myocytes, salivary gland, tongue, skin, trachea, pancreas
Subcellular
Localization
Not Known
Not Known
Binding Partners/
Associated Proteins
Neuregulin
Ebp1
SH2 domain of p85
Neuregulin-1
β-cellulin
Upstream
Activators
α and β isoforms of Heregulin-1/Neuregulin-1 (HRG/NRG-1α, HRG/NRG-1β)
α and β isoforms of Heregulin-2/ Neuregulin-2 (HRG/NRG-2α, HRG/NRG-2β)
Betacellulin (BTC) (B3670)
Heparin binding- EGF (HB-EGF) (SRP3052)
Epiregulin (EPR) (E8780)
Neuregulin-3 (NRG-3)
Neuregulin-4 (NRG-4)
Downstream
Activation
Grb-2/7-SOS
Shc
PI3K (P8615)
Shc
Grb-2-SOS
PI3K (P8615)
Activators Not Known
Not Known
Inhibitors Not Known
AEE-788
CI-1033 (C7249)
Selective
Activators
Not Known
Not Known
Physiological
Function
Involved in development of variety of tissues Interacts with neuregulins
NRG-2
NRG-3
Heparin-binding EGF-like growth factor  
Disease
Relevance
Malignant neoplasms of the breast, ovary, pancreas, lung, prostate, bladder, colon Role of ErbB4 in malignancies is not well established. However, it has been implicated in some tumors of the breast, prostate, ovary, brain, lung

 

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References