MAPK signaling cascade in papillary thyroid carcinoma

Schematic representation of the MAPK signaling cascade in papillary thyroid carcinoma. MAPK, also known as ERK, translocates to the nucleus and promotes cell division when it is phosphorylated by MEK, a serine/threonine kinase. Constitutive activation of this process is tumorigenic. MAPK phosphorylation is a relatively distal step in a sequential phosphorylation cascade that can begin with the activation of a tyrosine kinase, is followed by phosphorylation of RAS which activates BRAF, a serine/threonine kinase followed by MEK and MAPK phosphorylation. In papillary thyroid carcinoma, somatic genetic alterations at three of these steps activate this linear signaling cascade. A gene rearrangement creating a chimeric RET or TRK activates the initial tyrosine kinase step. Activating point mutations of either RAS or BRAF constitutively activates these proteins. The tyrosine kinase, RAS, and BRAF genetic alterations are usually mutually exclusive, suggesting that any single alteration is sufficient to play an early role in tumorigenesis.^[1,2]