Chemoprevention of Head and Neck Cancer by Green Tea Extract: EGCG—The Role of EGFR Signaling and “Lipid Raft”

Figure 2

A proposed mechanism of TGF-α/EGFR/ras-MAPK activation loop in HNSCC. TGF-α binding to EGFR leads to dimerization and phosphorylation on lipid rafts. Phosphorylation of Y1068 and Y1086 is required for Grab2 binding and consequent ras activation. Activated EGFR dimmer is internalized via clathrin-coated pit. Cbl and CIN85 (overexpressed in 40% of HNSCC samples) are recruited at pY1045 and facilitate EGFR internalization. Phosphorylation of S1046/1047 is also necessary for EGFR internalization, albeit the precise role remains elusive. Recent evidence suggests that TGF-α-bound EGFRs signal in the cytosol, activating ras-MAPK cascade. Ras-enriched small cytosolic nanoparticles, “rasosomes,” might contribute to this signaling. Internalized TGF-α-bound EGFRs are sorted to early endosome. TGF-α dissociates from EGFR in the acidic environment of endosome. Free EGFR is recycled back via fast recycling back pathway to plasma membrane and is activated by TGF-α in a autocrine manner, resulting in constitutive activation of TGF-α/EGFR/ras-MAPK.