Fig 1: Normal (left) and aberrant (right) signaling pathways in thyroid carcinoma. The normal MAPK/ERK signaling pathway starts with growth factors that activate the RTK. Upon activation, its two intracellular domains cross-phosphorylate each other at the tyrosine residues. These phosphorylated residues activate GRB2, which recruits SOS1 adapter protein. SOS1 activates RAS, which begins the cascade by activating RAF, then MEK, which phosphorylates ERK. Phosphorylated ERK translocates inside the nucleus and controls the normal cell cycle. In the aberrant signaling pathway controlling thyroid carcinomas, the activation of the MAPK/ERK pathway works without the RTK and growth factors. BRAFV600E mutant protein is constitutively activated and further supra-activates MEK and ERK. RAS mutations are also constitutively activated and subsequently activate RAF, MEK, and ERK. This leads to the increase of different nuclear transcription factors such as ELK-1, c-Fos, c-Myc, and a decrease of TTF-1 and PAX-8, which results in thyroid identity loss and RAI refractoriness. c-Myc can activate the transcription of TERT, or a TERT promoter mutation leads to cell immortalization. Mutant RAS can also decrease TP-53 via PI3K-AKT pathway, resulting in loss of tumor suppression and chaotic cell cycle.