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. This evidence concerns the gene PIK3CA and neoplasm.