Fig. 1.

Overview of the role of the biomarkers explored in the study on EGFR signaling. EGFR activating mutations located in the EGFR tyrosine kinase domain enhance cell growth and invasion via tyrosine phosphorylation and lead to the activation of mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositol 3-kinase (PI3K)-AKT pathways. Src homology 2 domain-containing phosphatase 2 (SHP2), a widely expressed cytoplasmic tyrosine phosphatase with two src homology (SH)2 domains, plays an essential role in most receptor-tyrosine kinase (RTK) signaling pathways. SHP2 function is required for MAPK pathway and activation of its downstream transcriptional targets. SHP2 activates several Src family kinases (SFKs), including Src as top hit. STAT3 can be activated not only by growth factor receptors, like EGFR, but also by interleukins, like IL-6. IL-6 is a glycoprotein which first binds to a-chain (IL-6R) and then recruits the b-chain (gp130) of the receptor. Subsequently, the IL-6/IL-6R complex initiates homodimerization of gp130, activates a cytoplasmic tyrosine kinase bound to gp130 and triggers signaling cascades through Janus-like kinase (JAK) and Src kinase. JAK2 mediates STAT3 phosphorylation and activation. The integrin-linked kinase (ILK) pathway activates beta-catenin (CTNNB1) signaling. ILK phosphorylates glycogen synthase kinase 3 (GSK3B) on serine 9 to inhibit its activity and induces the translocation of CTNNB1 into the nucleus. CTNNB1 regulates epithelial-mesenchymal transition (EMT). ILK expression is associated with IL-6 expression and can play an important role in mediating IL-6 function in EGFR-mutation positive lung cancer cells. Independently of STAT3, gp130 activates the Yes-Associated Protein (YAP1) oncoprotein through direct association with SFKs. Upon Src activation, several downstream Src binding partners are targeted for phosphorylation, including paxillin (PXN) on tyrosine 118. The tumor microenvironment-derived ligand hepatocyte growth factor (HGF) induces inter-receptor cross-talk of MET with (CUB) domain-containing protein-1 (CDCP1) or AXL.