|Somatic Mutations in Epidermal Growth Factor Receptor DataBase|
Click on the desired Exon to obtain information concerning the TK domain and specific exons.
Figure Legend: Tyrosine kinase sensitive and resistant somatic mutations of EGFR in NSCLC.
A diagrammatic representation of the epidermal growth factor receptor (EGFR) indicates the distribution of exons in the extracellular domain (EGF binding), transmembrane domain (TM) and intracellular domain (tyrosine kinase (TK) and autophosphorylation regions). The extracellular domain consists of 2 EGF binding (blue) cysteine-rich domains followed by a transmembrane domain. The tyrosine kinase domain lies within the intracellular domain (green). The TK domain (constituting exons 18–24) wherein somatic mutations in NSCLC have been identified and correlated with sensitivity to TKIs has been enlarged for clarity. Exon boundaries are indicated by the pointers with respective amino acid sequence locations identified.
The TK domain stretches from exon 18 to exon 24, somatic mutations are basically limited to exons 18-21 (687-875aa). Specific motifs within this region include the so called P-loop (nucleotide binding loop) GXGXXG motif in exon 18 (719-724aa); K745 and subsequent 3’ amino acids which is critical for adenosine phosphate binding; and a critical DGF (activation domain) motif in exon 21 (855-857aa); and a critical tyrosine at amino acid position 869.
Specifically targeted amino acids are indicated (most frequent somatic mutations per exon (≥1% total mutations)). Color coding for the mutations: green = somatic mutations typically responsive to TKIs; red = somatic mutations typically non-responsive to TKIs, and yellow-green = somatic mutations typically responsive to TKIs (with mixed response outcomes). Deletional-insertions centered on the region of LREAT account for approximately 47.6% of all mutation carriers. The second most common mutation is that of L858R located in exon 21 accounting for approximately 34% of all mutations. A mutational frequency greater than 1% is also found for the somatic mutations G719, L861 and T790 (with T790M being correlated with resistance to TKIs). Each of the most frequent somatic mutations target one of the aforementioned motifs within the TK domain.
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