Glial cell line-derived neurotrophic factor (GDNF), a ligand of RET tyrosine 
kinase, and its family ligands promote the survival and differentiation of a 
variety of neurons. Gene ablation studies have revealed that the GDNF-RET 
receptor system is essential for the development of kidney and peripheral 
neurons, including sympathetic, parasympathetic and enteric neurons. RET can 
activate various signaling pathways such as RAS/extracellular signal-regulated 
kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/AKT, p38 mitogen-activated 
protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways. These 
signaling pathways are activated via binding of adaptor proteins to 
intracellular tyrosine residues of RET phosphorylated by its own kinase 
activity. The RET is profoundly involved in the development of several human 
neuroendocrine diseases. The constitutive activation of the RET by somatic 
rearrangement with other partner genes or germ-line mutations causes a 
considerable population of human papillary thyroid carcinomas or multiple 
endocrine neoplasia (MEN) type 2A and 2B, respectively, whereas the dysfunction 
of RET by germ-line missense and/or nonsense mutations causes Hirschsprung's 
disease. Biological properties of mutant RET protein determine the disease 
phenotype. For example, the MEN 2B mutation alters the substrate specificity of 
RET tyrosine kinase and RET carrying the MEN 2B mutation hereby induces the 
different set of genes from that carrying the MEN 2A mutation. In this review, 
we describe the current knowledge about the molecular mechanism of RET 
activation in human neuroendocrine tumors as well as the physiological roles and 
signal transduction of RET tyrosine kinase.