Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities....

All of the cases of medullary thyroid carcinoma (MTC) express the RET receptor tyrosine kinase. In essentially all of the hereditary cases and 40% of the sporadic cases of MTC, the RET kinase is constitutively activated by mutation. This suggests that RET may be an effective therapeutic target for treatment of MTC. We show that the indolocarbazole derivatives, CEP-701 and CEP-751, inhibit RET i...

During prophase I of male meiosis, the sex chromosomes form a compact structure called XY body that associates with the nuclear membrane of pachytene spermatocytes. Ret Finger Protein is a transcriptional repressor, able to interact with both nuclear matrix-associated proteins and double-stranded DNA. We report the precise and unique localization of Ret Finger Protein in pachytene spermatocytes...

........................................................................................................12 1. LITERATURE REVIEW...............................................................................14 1.1 NEUROTROPHIC FACTORS ....................................................................................14 1.2 THE GDNF FAMILY OF NEUROTROPHIC FACTORS ...................................

The RET/PTC oncogene has been isolated almost twenty years ago. During these years, the research has given a final answer to several questions. In fact, it has been demonstrated that: a) RET/PTC is an early event in the process of thyroid carcinogenesis and has a critical role in the generation of the papillary carcinoma; b) RET/PTC activation is essentially restricted to the papillary histotyp...

During postnatal development, sympathetic neurons lose their dependence upon NGF for survival but continue to require NGF for soma and process growth and for development of a mature neurotransmitter phenotype. Although c-Ret is expressed in sympathetic neurons during this period, its function in these transitional processes is unclear. The level of Ret phosphorylation markedly increased with po...

The glial cell line-derived neurotrophic factor (GDNF) ligands (GDNF, Neurturin [NTN], and Persephin [PSP]) signal through a multicomponent receptor system composed of a high-affinity binding component (GFRalpha1-GFRalpha4) and a common signaling component (RET). Here, we report the identification of Artemin, a novel member of the GDNF family, and demonstrate that it is the ligand for the forme...

To decipher the molecular basis for RET kinase activation and oncogenic deregulation, we defined the temporal sequence of RET autophosphorylation by label-free quantitative mass spectrometry. Early autophosphorylation sites map to regions flanking the kinase domain core, while sites within the activation loop only form at later time points. Comparison with oncogenic RET kinase revealed that lat...

Establishment of connectivity between peripheral and central organs is essential for sensory processing by dorsal root ganglion (DRG) neurons. Using Ret as a marker for mechanoreceptive DRG neurons, we show that both central and peripheral projections of mechanoreceptive neurons are severely impaired in the absence of Ret. Death of DRG neurons in Ret-deficient mice can be rescued by eliminating...

OBJECTIVE We investigated directed therapy based on TFAP2C-regulated pathways to inform new therapeutic approaches for treatment of luminal breast cancer. BACKGROUND TFAP2C regulates the expression of genes characterizing the luminal phenotype including ESR1 and RET, but pathway cross talk and potential for distinct elements have not been characterized. METHODS Activation of extracellular s...