Fig. 2 |. Interactions between MAPK and cAMP signalling in thyroid cancer cells.
Thyroid cells are under the regulatory control of thyroid-stimulating hormone (TSH), acting through the TSH receptor (TSHR) to signal primarily through Gsα and adenylyl cyclase to increase intracellular cAMP levels. cAMP in turn activates protein kinase A (PKA), which phosphorylates substrates to ultimately regulate the growth and differentiated function of thyroid cells in part through inducing expression of the lineage transcription factors paired box 8 (PAX8) and forkhead box E1 (FOXE1), which regulate the expression of genes required for thyroid hormone biosynthesis (for example, sodium iodide symporter (NIS), thyroglobulin (TG), thyroid peroxidase (TPO) and TSHR). Activation of the MAPK pathway, through receptor tyrosine kinase (RTK) fusions, or RAS or BRAF mutations, impairs TSH–cAMP signalling at various nodes in the pathway24,102,105,270. This takes place by repressing expression of TSHR and inhibiting the catalytic activity of adenylyl cyclase, thus impairing PAX8-mediated and FOXE1-mediated transcription and inhibiting differentiated function in thyroid cancer cells. The figure illustrates the functional consequences of the BRAF-V600E mutation, highlighted with an asterisk.