Abstract
The RET (rearranged during transfection) proto-oncogene encodes a tyrosine kinase receptor involved in both multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome, and Hirschsprung disease (HSCR), a developmental defect of enteric neurons. We report here that the expression of RET receptor induces apoptosis. This pro-apoptotic effect of RET is inhibited in the presence of its ligand glial cell line-derived neurotrophic factor (GDNF). Furthermore, we present evidence that RET induces apoptosis via its own cleavage by caspases, a phenomenon allowing the liberation/exposure of a pro-apoptotic domain of RET. In addition, we report that Hirschsprung-associated RET mutations impair GDNF control of RET pro-apoptotic activity. These results indicate that HSCR may result from apoptosis of RET-expressing enteric neuroblasts.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis*
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Autonomic Nervous System Diseases / etiology
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Caspases / metabolism
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Drosophila Proteins*
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Enteric Nervous System / pathology
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Enzyme Activation
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Hirschsprung Disease / etiology*
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Hirschsprung Disease / genetics
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Ligands
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Nerve Growth Factors*
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Nerve Tissue Proteins / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Recombinant Proteins / metabolism
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Substrate Specificity
Substances
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Drosophila Proteins
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Ligands
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Nerve Growth Factors
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Nerve Tissue Proteins
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Proto-Oncogene Proteins
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Recombinant Proteins
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases
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Ret protein, Drosophila
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Caspases