Inactivation of over-expressed wild type EGFR by Cetuximab recombinant antibody Covalent tyrosine kinase inhibitors bind and inhibit wild-type EGF:EGFR dimers HSP90 is inactivated by binding to benzaquinoid ansamycins Covalent tyrosine kinase inhibitors bind and inactivate EGFR kinase domain mutant dimers resistant to non-covalent tyrosine kinase inhibitors Non-covalent tyrosine kinase inhibitors bind and inactivate sensitive ligand-responsive EGFR cancer mutants Binding of GRB2:SOS1 to p-EGFR mutants SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex with p-EGFR mutants) Binding of SHC1 to p-EGFR mutants Phosphorylation of SHC1 by p-EGFR mutants Phosphorylated SHC1 in complex with p-EGFR mutants recruits GRB2:SOS1 complex Spontaneous dimerization of ligand-responsive EGFR mutants Trans-autophosphorylation of activated ligand-responsive EGFR mutant dimers EGFRvIII mutant binds chaperone proteins HSP90 and CDC37. Ligand-independent dimerization of EGFRvIII mutant Trans-autophosphorylation of EGFRvIII mutant dimers Phosphorylation of CBL by ligand-responsive p-6Y-EGFR mutants Inefficient ubiquitination of ligand-responsive EGFR mutants by phosphorylated CBL Dissociation of phosphorylated PLC-gamma 1 from p-EGFR mutants Binding of CBL to phosphorylated ligand-responsive EGFR mutants SOS-mediated nucleotide exchange of RAS (mediated by GRB2:SOS1 in complex with phosphorylated SHC1 and p-EGFR mutants) Binding of GRB2:GAB1:PIK3R1 complex to p-EGFR mutants PLC-gamma 1 binds to p-EGFR mutants Phosphorylation of PLC-gamma 1 by p-EGFR mutants Binding of PI3K p110 subunit alpha (PIK3CA) to complex of GRB2:GAB1:PIK3R1 and p-EGFR mutants Conversion of PIP2 to PIP3 by PI3K bound to phosphorylated EGFR mutants Binding of EGF to ligand-responsive EGFR mutants EGF-induced dimerization of ligand-responsive EGFR mutants Binding of ligand-responsive EGFR mutants to chaperoning proteins HSP90 and CDC37 Signaling by constitutively active EGFR Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Gillespie, ME, 2011-11-07 Edited: Haw, R, 2011-11-07 Edited: Jassal, B, 2011-11-07 Edited: Matthews, L, 2011-11-07 Edited: Wu, G, 2011-11-07 Pubmed11087732 Pubmed12471035 Pubmed14718169 Pubmed15118073 Pubmed15269313 Pubmed15284455 Pubmed15837620 Pubmed16024644 Pubmed16187797 Pubmed16314626 Pubmed16777603 Pubmed16849543 Pubmed16969069 Pubmed17085664 Pubmed17177598 Pubmed17349580 Pubmed17646646 Pubmed17699773 Pubmed18511936 Pubmed19560417 Pubmed20033049 Reactome Database ID Release 431236382 Reactome, http://www.reactome.org ReactomeREACT_115852 Reviewed: Greulich, H, 2011-11-15 Reviewed: Savas, S, 2011-11-15 Signaling by EGFR is frequently activated in cancer through either genomic amplification of the EGFR locus, resulting in over-expression of the wild-type protein, or through activating mutations in the coding sequence of the EGFR gene, resulting in expression of a constitutively active mutant protein. Epidermal growth factor receptor kinase domain mutants are present in ~16% of non-small-cell lung cancers (NSCLCs), but are also found in other cancer types, such as breast cancer, colorectal cancer, ovarian cancer and thyroid cancer. EGFR kinase domain mutants harbor activating mutations in exons 18-21 which code for the kinase domain (amino acids 712-979) . Small deletions, insertions or substitutions of amino acids within the kinase domain lock EGFR in its active conformation in which the enzyme can dimerize and undergo autophosphorylation spontaneously, without ligand binding (although ligand binding ability is preserved), and activate downstream signaling pathways that promote cell survival (Greulich et al. 2005, Zhang et al. 2006, Yun et al. 2007, Red Brewer et al. 2009). In glioblastoma, the most prevalent EGFR mutation, present in ~25% of tumors, is the deletion of the ligand binding domain of EGFR, accompanied with amplification of the mutated allele, which results in over-expression of the mutant protein known as EGFRvIII. EGFRvIII mutant is not able to bind a ligand, but dimerizes and autophosphorylates spontaneously and is therefore constitutively active (Fernandes et al. 2001). Point mutations in the extracellular domain of EGFR are also frequently found in glioblastoma. Similar to kinase domain mutations, point mutations in the extracellular domain result in constitutively active EGFR proteins that signal in the absence of ligands, but ligand binding ability and responsiveness are preserved (Lee et al. 2006). Both EGFR kinase domain mutants and EGFRvIII mutant need to maintain association with the chaperone heat shock protein 90 (HSP90) for proper functioning (Shimamura et al. 2005, Lavictoire et al. 2003). CDC37 is a co-chaperone of HSP90 that acts as a scaffold and regulator of interaction between HSP90 and its protein kinase clients. CDC37 is frequently over-expressed in cancers involving mutant kinases and acts as an oncogene (Roe et al. 2004, reviewed by Gray Jr. et al. 2008). Over-expression of the wild-type EGFR or EGFR cancer mutants results in aberrant activation of downstream signaling cascades, namely RAS/RAF/MAP kinase signaling and PI3K/AKT signaling, and possibly signaling by PLCG1, which leads to increased cell proliferation and survival, providing selective advantage to cancer cells that harbor activating mutations in the EGFR gene (Sordella et al. 2004, Huang et al. 2007). While growth factor activated wild-type EGFR is promptly down-regulated by internalization and degradation, cancer mutants of EGFR demonstrate prolonged activation (Lynch et al. 2004). Association of HSP90 with EGFR kinase domain mutants negatively affects CBL-mediated ubiquitination, possibly through decreasing the affinity of EGFR kinase domain mutants for phosphorylated CBL, so that CBL dissociates from the complex upon phosphorylation and cannot perform ubiquitination (Yang et al. 2006, Padron et al. 2007). EGFRvIII mutant does not autophosorylate on the tyrosine residue Y1045, a docking site for CBL, and is therefore unable to recruit CBL ubiquitin ligase, which enables it to escape degradation (Han et al. 2006). Various molecular therapeutics are being developed to target aberrantly activated EGFR in cancer. Non-covalent (reversible) small tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, selectively bind kinase domain of EGFR, competitively inhibiting ATP binding and subsequent autophosphorylation of EGFR dimers. EGFR kinase domain mutants sensitive to non-covalent TKIs exhibit greater affinity for TKIs than ATP compared with the wild-type EGFR protein, and are therefore preferential targets of non-covalent TKI therapeutics (Yun et al. 2007). EGFR proteins that harbor point mutations in the extracellular domain also show sensitivity to non-covalent tyrosine kinase inhibitors (Lee et al. 2006). EGFR kinase domain mutants harboring small insertions in exon 20 or a secondary T790M mutation are resistant to reversible TKIs (Balak et al. 2006) due to increased affinity for ATP (Yun et al. 2008), and are targets of covalent (irreversible) TKIs that form a covalent bond with EGFR cysteine residue C397. However, effective concentrations of covalent TKIs also inhibit wild-type EGFR, causing severe side effects (Zhou et al. 2009). Hence, covalent TKIs have not shown much promise in clinical trials (Reviewed by Pao and Chmielecki in 2010). Recombinant monoclonal antibody Cetuximab acts as an antagonist of EGFR ligand binding, and is approved for the treatment of tumors that over-express wild-type EGFR receptor (Cunningham et al. 2004, Li et al. 2005, Burtness et al. 2005). PathwayStep3928 PathwayStep3929 PathwayStep3953 PathwayStep3952 PathwayStep3951 PathwayStep3950 PathwayStep3955 PathwayStep3954 PathwayStep3935 PathwayStep3934 PathwayStep3933 PathwayStep3932 PathwayStep3931 PathwayStep3930 PathwayStep3939 PathwayStep3938 PathwayStep3937 PathwayStep3936 PathwayStep3944 PathwayStep3943 PathwayStep3946 PathwayStep3945 PathwayStep3940 PathwayStep3942 PathwayStep3941 PathwayStep3948 PathwayStep3947 PathwayStep3949