RET and thyroid cancer: GFRα1–4 bind to the RET ligands GDNF, neurturin, artemin, and persephin, respectively, with high affinity and specificity, thereby forming a binary complex and stimulating RET kinase.193 The phosphorylation of RET kinase activates multiple downstream pathways, including the MAPK pathway, JAK/STAT pathway, PI3K/AKT/mTOR pathway, and PKC, which are associated with tumor cell proliferation, invasion, migration and survival.194,195 Mutations and rearrangements of the RET gene are commonly discovered in thyroid cancer.