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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. [Copyright &y& Elsevier]

Abstract: The glial cell line-derived neurotrophic factor (GDNF)/RET tyrosine kinase signaling pathway plays crucial roles in the development of the enteric nervous system (ENS) and the kidney. Tyrosine 1062 (Y1062) in RET is an autophosphorylation residue that is responsible for the activation of the PI3K/AKT and RAS/MAPK signaling pathways. Mice lacking signaling via Ret Y1062 show renal hypoplasia and hypoganglionosis of the ENS although the phenotype is milder than the Gdnf- or Ret-deficient mice. Sprouty2 (Spry2) was found to be an antagonist for fibroblast growth factor receptor (FGFR) and acts as an inhibitory regulator of ERK activation. Spry2-deficient mice exhibit hearing loss and enteric nerve hyperplasia. In the present study, we generated Spry2-deficient and Ret Y1062F knock-in (tyrosine 1062 is replaced with phenylalanine) double mutant mice to see if abnormalities of the ENS and kidney, caused by loss of signaling via Ret Y1062, are rescued by a deficiency of Spry2. Double mutant mice showed significant recovery of ureteric bud branching and ENS development in the stomach. These results indicate that Spry2 regulates downstream signaling mediated by GDNF/RET signaling complex in vivo. [ABSTRACT FROM AUTHOR]

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) define a new family of neurotrophic factors that play crucial roles in survival and differentiation of various neurons. Recent studies demonstrated that GDNF and NTN use a multicomponent receptor system in which glycosyl-phosphatidylinositol (GPI)-linked cell surface proteins and Ret receptor tyrosine kinase function as the ligand-binding and signalling components, respectively. In the present study, we investigated the role of Ca2+ ions for biochemical and biological activities of Ret because Ret has a unique structure of the extracellular domain with the cadherin-like motif. The results demonstrated that Ca2+ ions might be required for the complex formation of Ret and GDNF or NTN that induces Ret oligomerization and autophosphorylation. Full morphological differentiation of neuroblastoma cells by these neurotrophic factors was also Ca2+-dependent. These findings thus suggested that, in addition to GPI-linked cell surface proteins, Ca2+ ions are components of the signal transducing complex formed by Ret and GDNF protein family. [ABSTRACT FROM AUTHOR]