Inducible dimerization of RET reveals a specific AKT deregulation in oncogenic signaling.
Dominant-activating mutations in the RET (rearranged during transfection) proto-oncogene, a receptor tyrosine kinase, are causally associated with the development of multiple endocrine neoplasia type 2A (MEN2A) syndrome. Such oncogenic RET mutations induce its ligand-independent constitutive activation, but whether it spreads identical signaling to ligand-induced signaling is uncertain. To address this question, we designed a cellular model in which RET can be activated either by its natural ligand, or alternatively, by controlled dimerization of the protein that mimics MEN2A dimerization. We have shown that controlled dimerization leaves proximal RET signaling intact but impacts substantially on the tuning of the distal AKT kinase activation (delayed and sustained). In marked contrast, distal activation of ERK remained unaffected. We further demonstrated that specific temporal adjustment of ligand-induced AKT activation is dependent upon a lipid-based cholesterol-sensitive environment, and this control step is bypassed by MEN2A RET mutants. Therefore, these studies revealed that MEN2A mutations propagate previously unappreciated subtle differences in signaling pathways and unravel a role for lipid rafts in the temporal regulation of AKT activation.
Frêche
Barbara
B
Laboratoire de Génétique moléculaire, Signalisation et Cancer, Unité Mixte de Recherche (UMR) 5201, Facultéde Médecine, 8 avenue Rockefeller, 69 373 LYON Cedex 08, France.
Guillaumot
Patricia
P
Charmetant
Julie
J
Pelletier
Ludivine
L
Luquain
Celine
C
Christiansen
Dale
D
Billaud
Marc
M
Manié
Serge N
SN
D019281:Dimerization; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018813:Multiple Endocrine Neoplasia Type 2a / Q000378:metabolism*; D009154:Mutation; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C494989:Gfra1 protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C495001:Ret protein, rat; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3