EGF/EGFR signaling pathway (WP437)

Epidermal growth factor receptor (EGFR) also known as ErbB1/HER1 is a member of the ErbB family of receptor tyrosine kinases which also includes ErbB2 (Neu, HER2), ErbB3 (HER3) and ErbB4 (HER4). Several ligands such as epidermal growth factor, transforming growth factor-alpha, epigen, amphiregulin, betacellulin, heparin-binding EGF and epiregulin are known to specifically bind to EGFR. Epidermal growth factor (EGF) is one of the high affinity ligands of EGFR. EGF/EGFR system induces growth, differentiation, migration, adhesion and cell survival through various inter-acting signaling pathways. The binding of EGF to the extracellular domain of EGFR induces the dimerization, activation of intrinsic kinase activity and subsequent autophosphorylation of EGFR at multiple residues in the cytoplasmic region such as Tyr 1092, Tyr 1172, Tyr 1197, Tyr 1110, Tyr 1016). Activated EGFR recruits various cytoplasmic proteins which transduce and regulate the EGFR function. The proteins recruited to active EGFR include many Src homology 2 (SH2) and phosphotyrosine binding (PTB) domain containing proteins which binds to the tyrosine phosphorylated residues in EGFR, enzymes which act on EGFR and also various EGFR substrates. One of the adapter proteins, GRB2, binds to the phosphotyrosine residue at 1068 and recruits SOS to the membrane. SOS activates GDP/GTP exchange which recruits RAF to the membrane. RAF phosphorylates MEKs, which then activates the extracellular signal regulated kinase (ERK). ERK activates a number of transcriptional regulators to induce cell growth and proliferation. GRB2 or other adaptor proteins such as GABs recruits PI3Ks, another major mediator of EGFR signaling. PI3Ks convert Phosphatidylinositol-4,5-bisphosphate (PIP2) to Phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 binds to PH domain of AKT and recruits it to plasma membrane. PDK1 phosphorylates AKT which in turn regulate the activity of various proteins that mediate cell survival. EGFR also activate phospholipase C which hydrolyses PIP2 to generate Inositol trisphosphate (IP3) and 1,2-Diacylglycerol (DAG). IP3 induces the release of Ca2+ from endoplasmic reticulum to activate calcium regulated pathways. DAG activates protein kinase C pathway. One of the signaling modules regulated by PKC in EGFR pathway is the NFKB module. The protein SRC is a key player in the activation of various pathways such as RAS, PLC and also the STAT proteins in various cells. Other signaling modules activated by EGFR include the FAK, JNK, p38MAPK and ERK5 modules. EGFR induces the JNK pathway through the activation of G proteins such as RAC and CDC42 which recruits JNK kinases as well as regulate the actin polymerization. EGFR also translocates from the plasma membrane to other cellular compartments including nucleus where it directly regulate the expression of several genes in cooperation with other transcriptional regulators such as STATs, PCNA and E2F family of proteins. Being a growth, differentiation and cell survival factor; mutations and overexpression of EGFR and also the defective regulation of its signal transduction pathways has been established to be associated with oncogenesis. Thus, EGFR and its signaling components are promising targets for effective therapy for various cancers. There are several proteins which have been reported to regulate the EGFR signaling such as CBL, CSK, PKC and PTEN which promotes endocytosis or reduction in the EGFR activity or its signaling mediators. The major endocytic pathway of EGFR is established to be the clathrin coated pits which delivers them to endosomes. The endosomal pathway recycles the membraneous form of EGFR or form multivesicular bodies (MVB) and fuse with lysosomes for to the degradation pathway. Please access this pathway at [http://www.netpath.org/netslim/EGFR1_pathway.html NetSlim] database. If you use this pathway, please cite the following paper: Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. Genome Biology. 11:R3. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP437 CPTAC Assay Portal]
last edited

Authors

A.Pandey, MaintBot, Nsalomonis, Michiel, AlexanderPico, Khanspers, NetPath, Christine Chichester, Zari, L Dupuis, Egonw, Eweitz, and Finterly

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: epidermal growth factor/neuregulin signaling pathway

Participants

Label Type Compact Identifier
SHC1 Protein ncbigene:6464
STAT5A Protein ncbigene:6776
RALA Protein ncbigene:5898
NEDD4 Protein ncbigene:4734
ELK4 Protein ncbigene:2005
MAPK1 Protein ncbigene:5594
MAPK8 Protein ncbigene:5599
ARHGEF1 Protein ncbigene:9138
STMN1 Protein ncbigene:3925
STAT1 Protein ncbigene:6772
EPS15L1 Protein ncbigene:58513
SH3GL3 Protein ncbigene:6457
EGF Protein ncbigene:1950
INPP5D Protein ncbigene:3635
PTPN5 Protein ncbigene:84867
ATF1 Protein ncbigene:466
GRB10 Protein ncbigene:2887
ERRFI1 Protein ncbigene:54206
GRIM19 Protein ncbigene:51079
MAP3K1 Protein ncbigene:4214
PTK6 Protein ncbigene:5753
RPS6KA2 Protein ncbigene:6196
CSK Protein ncbigene:1445
PCNA Protein ncbigene:5111
KRAS Protein ncbigene:3845
LIMK2 Protein ncbigene:3985
RASA1 Protein ncbigene:5921
ARF6 Protein ncbigene:382
IQGAP1 Protein ncbigene:8826
EGFR Protein ncbigene:1956
SP1 Protein ncbigene:6667
BRAF Protein ncbigene:673
DOK2 Protein ncbigene:9046
PTPRR Protein ncbigene:5801
CRK Protein ncbigene:1398
SH2D2A Protein ncbigene:9047
MAPK9 Protein ncbigene:5601
NOS3 GeneProduct ncbigene:4846
RPS6KA3 Protein ncbigene:6197
RIN1 Protein ncbigene:9610
CAV2 Protein ncbigene:858
E2F1 Protein ncbigene:1869
VAV2 Protein ncbigene:7410
SOS2 Protein ncbigene:6655
PTPN12 Protein ncbigene:5782
MTOR Protein ncbigene:2475
NCK2 Protein ncbigene:8440
MAP3K3 Protein ncbigene:4215
RALGDS Protein ncbigene:5900
VAV3 Protein ncbigene:10451
CAMK2A Protein ncbigene:815
STAT3 Protein ncbigene:6774
MAPK3 Protein ncbigene:5596
SOS1 Protein ncbigene:6654
GAB2 Protein ncbigene:9846
RAP1A Protein ncbigene:5906
TWIST1 Rna ncbigene:7291
JAK1 Protein ncbigene:3716
CDC42 Protein ncbigene:998
NCOA3 Protein ncbigene:8202
ATXN2 Protein ncbigene:6311
RAB5A Protein ncbigene:5868
RPS6KB1 Protein ncbigene:6198
MAPK14 Protein ncbigene:1432
ASAP1 Protein ncbigene:50807
SYNJ1 Protein ncbigene:8867
MAP2K1 Protein ncbigene:5604
RAF1 Protein ncbigene:5894
EPN1 Protein ncbigene:29924
MYBL2 Rna ncbigene:4605
NCK1 Protein ncbigene:4690
STAMBP Protein ncbigene:10617
CAV1 Protein ncbigene:857
STAM2 Protein ncbigene:10254
SHC1 Protein ncbigene:6464
HGS Protein ncbigene:9146
MAP2K2 Protein ncbigene:5605
CREB1 Protein ncbigene:1385
EGFR Protein ncbigene:1956
PLCG1 Protein ncbigene:5335
ERBB2 Protein ncbigene:2064
SPRY2 Protein ncbigene:10253
INPPL1 Protein ncbigene:3636
AURKA Rna ncbigene:6790
EIF4EBP1 Protein ncbigene:1978
MAP4K1 Protein ncbigene:11184
RICTOR Protein ncbigene:253260
USP6NL Protein ncbigene:9712
RPS6KA5 Protein ncbigene:9252
PTK2B Protein ncbigene:2185
PIK3R2 Protein ncbigene:5296
PLD2 Protein ncbigene:5338
EPS8 Protein ncbigene:2059
RAC1 Protein ncbigene:5879
ABI1 Protein ncbigene:10006
PLSCR1 Protein ncbigene:5359
EGFR Protein ncbigene:1956
PIK3R1 Protein ncbigene:5295
MEF2D Protein ncbigene:4209
GAB1 Protein ncbigene:2549
PLCE1 Protein ncbigene:51196
PLD1 Protein ncbigene:5337
DNM1 Protein ncbigene:1759
JUN Protein ncbigene:3725
PIAS3 Protein ncbigene:10401
SH3GL2 Protein ncbigene:6456
RPS6KA1 Protein ncbigene:6195
ROCK1 Protein ncbigene:6093
MAP3K4 Protein ncbigene:4216
PRKCD Protein ncbigene:5580
AP2B1 Protein ncbigene:163
AKT1 Protein ncbigene:207
FOXO1 Protein ncbigene:2308
VAV1 Protein ncbigene:7409
PRKCZ Protein ncbigene:5590
RALB Protein ncbigene:5899
FOS Protein ncbigene:2353
PRKCI Protein ncbigene:5584
PRKCA Protein ncbigene:5578
SRC Protein ncbigene:6714
ITCH Protein ncbigene:83737
ABL1 Protein ncbigene:25
RALBP1 Protein ncbigene:10928
MAPK7 Protein ncbigene:5598
REPS2 Protein ncbigene:9185
JUND Protein ncbigene:3727
GRB2 Protein ncbigene:2885
EPS15 Protein ncbigene:2060
USP8 Protein ncbigene:9101
PLSCR1 Protein ncbigene:5359
AP2A1 Protein ncbigene:160
HRAS Protein ncbigene:3265
PDPK1 Protein ncbigene:5170
IQSEC1 Protein ncbigene:9922
PEBP1 Protein ncbigene:5037
SH3KBP1 Protein ncbigene:30011
TNK2 Protein ncbigene:10188
PTPN11 Protein ncbigene:5781
AP2S1 Protein ncbigene:1175
PRKCB Protein ncbigene:5579
COX2 GeneProduct ncbigene:4513
FOXO4 Protein ncbigene:4303
FOSB Protein ncbigene:2354
PTEN Protein ncbigene:5728
NEDD8 Protein ncbigene:4738
STAM Protein ncbigene:8027
GJA1 Protein ncbigene:2697
CRKL Protein ncbigene:1399
JAK2 Protein ncbigene:3717
MAP2K5 Protein ncbigene:5607
BCAR1 Protein ncbigene:9564
MAP3K2 Protein ncbigene:10746
ELK1 Protein ncbigene:2002
STAT5B Protein ncbigene:6777
PIK3C2B Protein ncbigene:5287
STXBP1 Protein ncbigene:6812
EGFR Protein ncbigene:1956
EGFR Protein ncbigene:1956
CBLB Protein ncbigene:868
CBL Protein ncbigene:867
CBLC Protein ncbigene:23624
SRC Protein ncbigene:6714
GRB2 Protein ncbigene:2885
SOS1 Protein ncbigene:6654
RALBP1 Protein ncbigene:10928
CBLB Protein ncbigene:868
CBL Protein ncbigene:867
CBLC Protein ncbigene:23624
PLD1 Protein ncbigene:5337
PAK1 Protein ncbigene:5058
STAT3 Protein ncbigene:6774
STAT1 Protein ncbigene:6772
STAT5B Protein ncbigene:6777
STAT5A Protein ncbigene:6776
CFL1 Protein ncbigene:1072
PTK2 Protein ncbigene:5747
EGF Protein ncbigene:1950
AP2M1 Protein ncbigene:1173
PIAS3 Protein ncbigene:10401
MEF2A Protein ncbigene:4205
SRC Protein ncbigene:6714
PXN Protein ncbigene:7837
HRAS Protein ncbigene:3265
VAV2 Protein ncbigene:7410
SP1 Protein ncbigene:6667
EPS8 Protein ncbigene:2059
MEF2C Protein ncbigene:4208
RPS6KA3 Protein ncbigene:6197
MAPK3 Protein ncbigene:5596
MAPK1 Protein ncbigene:5594
MAPK9 Protein ncbigene:5601
MAPK8 Protein ncbigene:5599
MAPK7 Protein ncbigene:5598
MAP2K2 Protein ncbigene:5605
MAP2K1 Protein ncbigene:5604

References