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The growth arrest-specific gene 1 (Gas1) protein has been proposed to function during development as an inhibitor of growth and a mediator of cell death and is also re-expressed in adult neurons during excitotoxic insult. Here we have demonstrated that the Gas1 protein shows high structural similarity to the glial cell-derived neurotrophic factor (GDNF) family receptors alpha, which mediate GDNF responses through the receptor tyrosine kinase Ret. We found that Gas1 binds Ret in a ligand-independent manner and sequesters Ret in lipid rafts. Signaling downstream of Ret is thus modified through a mechanism that involves the adaptor protein Shc as well as ERK, eventually blocking Akt activation. Consequently, when Gas1 is induced, Ret-mediated GDNF-dependent survival effects are compromised.

Original publication




Journal article


J Biol Chem

Publication Date





14330 - 14339


Amino Acid Sequence, Animals, Cell Cycle Proteins, DNA-Binding Proteins, GPI-Linked Proteins, Glial Cell Line-Derived Neurotrophic Factors, Humans, Lipids, Membrane Microdomains, Membrane Proteins, Mice, Models, Molecular, Molecular Sequence Data, Nuclear Proteins, Plasmids, Rats, Sequence Homology, Amino Acid, Signal Transduction