Gas1 is related to the glial cell-derived neurotrophic factor family receptors alpha and regulates Ret signaling.
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.
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnologia, Consejo Superior Investigaciones Cientificas, 28049 Madrid, Spain.
J Ruben
JR
Cabrera
Luis
L
Sanchez-Pulido
Ana M
AM
Rojas
Alfonso
A
Valencia
Santos
S
Mañes
Jose R
JR
Naranjo
Britt
B
Mellström
D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D058851:GPI-Linked Proteins; D051098:Glial Cell Line-Derived Neurotrophic Factors / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D021962:Membrane Microdomains / Q000737:chemistry; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; D051098:Glial Cell Line-Derived Neurotrophic Factors; D008055:Lipids; D008565:Membrane Proteins; D009687:Nuclear Proteins; C096192:GAS1 protein, human; C064419:TRIM27 protein, human; D000070584:Tripartite Motif Proteins