Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
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Target Concepts:
Gene/Protein
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Query: UMLS:C0030567 (
Parkinson's disease
)
63,064
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Rearranged during transfection, RET, is a receptor tyrosine kinase expressed in neural crest derived cell lineages. RET is activated by dimerisation facilitated by its binding to the heterodimeric complex formed by Glial cell-derived neurotrophic factor (GDNF) -family ligand (GFL) and GNDF-family receptor (GFR). Both GDNFs and their co-receptors are a small protein family of four members. RET kinase mediated signaling can lead to survival, cell growth, differentiation, and migration. Pharmaceutically RET is of interest due to its involvement in several disease conditions. Oncogenic RET activation by mutations or rearragements predisposes to cancers like
multiple endocrine neoplasia
type 2 (A and B) and medullary thyroid carcinoma. Loss-of-function mutations in RET are a strong susceptibility factor for Hirschsprung disease, which is characterized by lack of ganglion cells in gastrointestinal tract. All the GFLs promote neuronal survival and GDNF is one of the most potent neurotrophic factors for dopaminergic neurons. Therefore, the neuroprotective capacity of RET activation to override the apoptotic program in neurodegenerative diseases, like in dying midbrain dopaminergic neurons in
Parkinson's disease
, is of great interest. This article reviews the recent international patents on modulation of RET kinase activity by small-molecule and peptide-based agonists and antagonists.
...
PMID:Recent inventions on receptor tyrosine kinase RET modulation. 1907 52
The receptor tyrosine kinase RET is essential in a variety of cellular processes. RET gain-of-function is strongly associated with several cancers, notably
multiple endocrine neoplasia
type 2A (
MEN
2A), while RET loss-of-function causes Hirschsprung's disease and
Parkinson's disease
. To investigate the activation mechanism of RET as well as to enable drug development, over-expressed recombinant protein is needed for in vitro functional and structural studies. By comparing insect and mammalian cells expression of the RET extracellular domain (RET
ECD
), we showed that the expression yields of RET
ECD
using both systems were comparable, but mammalian cells produced monomeric functional RET
ECD
, whereas RET
ECD
expressed in insect cells was non-functional and multimeric. This was most likely due to incorrect disulfide formation. By fusing an Fc tag to the C-terminus of RET
ECD
, we were able to produce, in HEK293T cells, dimeric oncogenic RET
ECD
(C634R) for the first time. The protein remained dimeric even after cleavage of the tag via the cysteine disulfide, as in full-length RET in the context of
MEN
2A and related pathologies. Our work thus provides valuable tools for functional and structural studies of the RET signaling system and its oncogenic activation mechanisms.
...
PMID:Expression and purification of the extracellular domain of wild-type humanRET and the dimeric oncogenic mutant C634R. 3277 9
