EGF/EGFR signaling

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]

表皮生长因子受体（EGFR），亦称ErbB1/HER1，为ErbB家族受体酪氨酸激酶成员之一，该家族还包括ErbB2（Neu、HER2）、ErbB3（HER3）和ErbB4（HER4）。多种配体，如表皮生长因子、转化生长因子-α、表观、双调蛋白、β-细胞素、肝素结合EGF和表皮调节素等，已知能够特异性地结合到EGFR。表皮生长因子（EGF）是EGFR的高亲和力配体之一。EGF/EGFR系统通过多种相互作用的信号通路诱导生长、分化、迁移、粘附和细胞存活。EGF与EGFR的细胞外结构域结合，引起二聚化、固有激酶活性的激活以及EGFR在细胞质区域的多个位点（如Tyr 1092、Tyr 1172、Tyr 1197、Tyr 1110、Tyr 1016）的后续自磷酸化。激活的EGFR募集各种细胞质蛋白，这些蛋白能够转导并调节EGFR的功能。募集到激活的EGFR的蛋白包括许多Src同源2（SH2）和磷酸酪氨酸结合（PTB）结构域含有蛋白，这些蛋白结合到EGFR中磷酸化的酪氨酸残基，作用于EGFR的酶，以及各种EGFR底物。其中一种适配蛋白GRB2结合到1068位的磷酸酪氨酸残基，并募集SOS到膜上。SOS激活GDP/GTP交换，募集RAF到膜上。RAF磷酸化MEKs，随后激活细胞外信号调节激酶（ERK）。ERK激活多种转录调控因子，诱导细胞生长和增殖。GRB2或其他适配蛋白如GABs募集PI3Ks，这是EGFR信号传导的另一主要介质。PI3Ks将磷脂酰肌醇-4，5-二磷酸（PIP2）转化为磷脂酰肌醇-3，4，5-三磷酸（PIP3）。PIP3结合到AKT的PH结构域，并将其募集到质膜。PDK1磷酸化AKT，进而调节介导细胞存活的多种蛋白的活性。EGFR还激活磷脂酶C，该酶将PIP2水解为肌醇三磷酸（IP3）和1，2-二酰甘油（DAG）。IP3诱导内质网释放Ca2+，以激活钙调节通路。DAG激活蛋白激酶C通路。在EGFR通路中，蛋白激酶C调节的信号模块之一是NFKB模块。蛋白SRC在激活多种通路如RAS、PLC以及多种细胞中的STAT蛋白中扮演关键角色。由EGFR激活的其他信号模块包括FAK、JNK、p38MAPK和ERK5模块。EGFR通过激活G蛋白如RAC和CDC42，进而募集JNK激酶并调节肌动蛋白聚合，诱导JNK通路。EGFR还从质膜转移到其他细胞区室，包括细胞核，在与其他转录调控因子如STATs、PCNA和E2F蛋白家族蛋白的合作下，直接调节多个基因的表达。作为生长、分化和细胞存活因子，EGFR及其信号转导通路的突变和过表达，以及其调节缺陷，已被确立与肿瘤发生相关。因此，EGFR及其信号组分是治疗各种癌症的有效治疗靶点。已报道存在多种蛋白调节EGFR信号传导，如CBL、CSK、PKC和PTEN，这些蛋白促进内吞作用或降低EGFR活性及其信号介导物的活性。EGFR的主要内吞通路是已确立的网格蛋白包被的窝，将其递送到内体。内体通路回收EGFR的膜形式或形成多泡体（MVB），并与溶酶体融合，进入降解途径。请访问[http://www.netpath.org/netslim/EGFR1_pathway.html NetSlim]数据库获取此通路信息。如使用此通路，请引用以下论文：Kandasamy, K. 等人 (2010). NetPath：一个经过编纂的信号转导通路公共资源。《基因组生物学》。11：R3。该通路上的蛋白可通过[https://assays.cancer.gov/available_assays?wp_id=WP437 CPTAC检测门户]进行靶向检测。