Fig. 1.

The mitogen-activated protein kinase (MAPK) signaling pathway is physiologically activated by binding of growth factors to receptor tyrosine kinases (RTKs), such RET and NTRK, resulting in receptor dimerization and activation via autophosphorylation of tyrosine residues in the intracellular domain. The activated receptor, through a series of adaptor proteins, leads to activation of RAS located at the inner face of the plasma membrane. The activated RAS binds to and recruits RAF proteins (mainly BRAF in thyroid follicular cells) to the plasma membrane. Activated BRAF phosphorylates and activate the mitogen-activated protein kinase/ERK kinase (MEK), which in turn phosphorylates and activates the extracellular-signal-regulated kinase (ERK). Activated ERK translocates into the nucleus, where it regulates transcription of the genes involved in cell differentiation, proliferation and survival. Alterations of this pathway in thyroid cancer can occur at different levels as a result of point mutation or rearrangement involving the RET, RAS, and BRAF genes.