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. <i>Genome Biology</i>. 11:R3. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP437 CPTAC Assay Portal] EGFR phosphorylates GAP at Tyr-460 in R1hER cells EGF stimulates the interaction between EGFR and GAP in A341 cells. JUND interacts with FOS upon stimulation of EGFR with EGF in JEG3 cells. PLSCR1 interacts with EGFR upon stimulation of EGF receptor with EGF in A431 cells. EGF stimulates the interaction between EGFR and PTK6 in HB4a cells. EGF stimulates the interacts of EGFR and ATXN2 in mouse brain. EGFR induced phosphorylation of JAK1 under stimulation as established in HER14 cells ( wild) and NIH 3T3 cells ( mutant). Stimulation of EGF receptor with EGF abrogates receptor endocytosis through interaction of C-cbl with hSPRY2 in COS-1 cells. SHP2 dephosphorylates EGFR phosphorylated at Tyr 992 EGFR interacts CAV1 Phosphorylation of EPS8 by EGFR under stimulation in NIH-3T3 cells. EGF stimulates the interaction between EGFR and EPS8 in 3T3 cells. INPPL1 interacts with EGFR upon stimulation of EGFR with EGF in COS7 cells. 10788507, 8596638, 14665621 The extracellular domain of EGFR interacts with EGF to form a receptor complex structure containing EGF.EGFR complex in a 2:2 stoichiometry. EGFR interacts with STAT5B upon stimulation of EGFR with EGF in human hepatocytes. EGFR phosphorylates STAT5B at Tyr-699, Tyr-725, Tyr-740 and Tyr-743 in HEK293 cells. EGFR interacts with GRB10 upon stimulation of EGF receptor with EGF in mouse 3T3-L1 cells. EGFR phosphorylates PLD2 at Tyr-11 in HEK293 cells. EGF stimulates the interaction between EGFR and PLD2 in HEK293 cells. SRC phosphorylates PLSCR1 at Tyr-69 and Tyr-74 upon EGF receptor stimulation in A431 cells. EGF stimulates the interaction between EGFR and CSK in HeLa cells. PLSCR1 interacts with SHC1 upon stimulation of EGF receptor with EGF in A431 cells. EGFR induced phosphorylation of JAK2 in PC12 cells under stimulation. STAT1 interacts with STAT3 upon stimulation of EGFR with EGF in HEK293 cells. PRKCI interacts with ERK5 upon EGF stimulation in HEK293 cells. EGFR phosphorylates VAV2 at Tyr-142, Tyr-159 and Tyr-172 in COS7 and HeLa S3 cells. EGF stimulates the interaction between EGFR and VAV2 in NIH3T3 cells and COs-7 cells. EGFR phosphorylates EPS15 at Tyr-850 in COS7 and HeLa cells respectively. EPS15 interacts with EGFR upon EGF stimulation in HER14 cells. RAF1 phosphorylates MEK1 at Ser-218 ans Ser-222 upon stimulation of EGF receptor in NIH3T3 and HeLa cells respectively. RAF1 interacts with MAP2K1 upon stimulation of EGFR with EGF in 293T cells. SRC phosphorylates EGFR at Tyr869 and 1125 in NeoR and 5HR cells Ubiquitination of EGFR by CBLB in MDA-MB-468 breast cancer cells under EGF stimulation. EGF stimulates the interaction between EGFR and SRC in COS and NIH 3T3 cells CBL interacts with EGFR upon stimulation of EGFR with EGF in 16E6-P mammary epithelial cells and HEK cells EGFR interacts with NCK1 and NCK2 upon stimulation of EGFR with EGF in A431, HER14 cells. PAK1 phosphorylates NCOA3 and this phosphorylation is critical for its interaction with EGFR and FAK in HeLa and 293T cells. 20159588, 20159552 [20159552] 12953068 15828871 11687594 15314609 19534553 Phosphorylation of EPS8 by EGFR under stimulation in NIH-3T3 cells. EGF stimulates the interaction between EGFR and EPS8 in 3T3 cells. Ubiquitination of EGFR by CBLB in MDA-MB-468 breast cancer cells under EGF stimulation. Binding of EGF to EGFR induces their dimerisation and autophosphorylation at Tyr-1092, Tyr-1172, Tyr-1197, Tyr-1110 and Tyr-1016 in various cells. 3494473, 8639530, 2783412, 3257758, 1988447, 1856216, 19531499 3494473, 8639530, 2783412, 3257758, 1988447, 1856216, 19531499 epidermal growth factor/neuregulin signaling pathway PW:0000170 Pathway Ontology