Intracellular RET signaling pathways activated by GDNF.

Activation of REarranged during Transfection (RET) proto-oncogene is responsible for various human cancers such as papillary and medullary thyroid carcinomas and non-small cell lung carcinomas. RET activation in these tumors is caused by point mutations or gene rearrangements, resulting in constitutive activation of RET tyrosine kinase. Physiologically, RET is activated by glial cell line-derived neurotrophic factor (GDNF) ligands that bind to coreceptor GDNF family receptor alphas (GFRαs), leading to RET dimerization. GDNF-GFRα1-RET signaling plays crucial roles in the development of the enteric nervous system, kidney and lower urinary tract as well as in spermatogenesis. Intracellular tyrosine phosphorylation in RET and recruitment of adaptor proteins to phosphotyrosines are essential for various biological functions. Significance of intracellular RET signaling pathways activated by GDNF is discussed and summarized in this review.