Activation of the Erk8 Mitogen-activated Protein (Map) Kinase by Ret/Ptc3, a Constitutively Active Form of the Ret Proto-oncogene.
From: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università degli Studi di Napoli Federico II, Via Pansini 5, 80131 Naples, Italy.
The Journal of biological chemistry
- Publish Date: Apr 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 15
- Pages: 10567-76
- Medium: Print
- Language: English
- Citation (JAMA): Iavarone Carlo, Acunzo Mario, Carlomagno Francesca, et al. Activation of the Erk8 Mitogen-activated Protein (Map) Kinase by Ret/Ptc3, a Constitutively Active Form of the Ret Proto-oncogene.. J. Biol. Chem. Apr 2006;281:10567-76
Abstract
Mitogen-activated protein (MAP) kinases have a central role in several biological functions, including cell adhesion and spreading, chemotaxis, cell cycle progression, differentiation, and apoptosis. Extracellular signal-regulated kinase 8 (Erk8) is a large MAP kinase whose activity is controlled by serum and the c-Src non-receptor tyrosine kinase. Here, we show that RET/PTC3, an activated form of the RET proto-oncogene, was able to activate Erk8, and we demonstrate that such MAP kinase participated in RET/PTC3-dependent stimulation of the c-jun promoter. By using RET/PTC3 molecules mutated in specific tyrosine autophosphorylation sites, we characterized Tyr(981), a known binding site for c-Src, as a major determinant of RET/PTC3-induced Erk8 activation, although, surprisingly, the underlying mechanism did not strictly depend on the activity of Src. In contrast, we present evidence that RET/PTC3 acts on Erk8 through Tyr(981)-mediated activation of c-Abl. Furthermore, we localized the region responsible for the modulation of Erk8 activity by the RET/PTC3 and Abl oncogenes in the Erk8 C-terminal domain. Altogether, these results support a role for Erk8 as a novel effector of RET/PTC3 and, therefore, RET biological functions.
Mesh Headings (Keywords): Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Blotting, Western, Cell Line, Cell Line, Tumor, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Genes, Reporter, Genetic Vectors, Humans, MAP Kinase Signaling System, Mice, Molecular Sequence Data, Mutation, Phosphorylation, Promoter Regions (Genetics), Protein Binding, Protein Structure, Tertiary, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-ret, Signal Transduction, Thyroid Neoplasms, Transfection, Tyrosine, src-Family Kinases
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