Activation of Anaplastic Lymphoma Kinase Receptor Tyrosine Kinase Induces Neuronal Differentiation through the Mitogen-activated Protein Kinase Pathway

Anaplastic lymphoma kinase (ALK) is a novel neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems, suggesting a role in its normal development and function. To determine whether ALK could play a role i...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-03, Vol.276 (12), p.9526-9531
Main Authors: Souttou, Boussad, Carvalho, Nicole Brunet-De, Raulais, Daniel, Vigny, Marc
Format: Article
Language:English
Subjects:
Anaplastic Lymphoma Kinase
Animals
Base Sequence
Cell Division
DNA Primers
Enzyme Activation
Enzyme Inhibitors - pharmacology
Flavonoids - pharmacology
Humans
MAP Kinase Signaling System
Neurons - cytology
PC12 Cells
Phosphorylation
Protein-Tyrosine Kinases - chemistry
Protein-Tyrosine Kinases - metabolism
Rats
Receptor Protein-Tyrosine Kinases
Tyrosine - metabolism
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Summary:Anaplastic lymphoma kinase (ALK) is a novel neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems, suggesting a role in its normal development and function. To determine whether ALK could play a role in neuronal differentiation, we established a model system that allowed us to mimic the normal activation of this receptor. We expressed, in PC12 cells, a chimeric protein in which the extracellular domain of the receptor was replaced by the mouse IgG 2b Fc domain. The Fc domain induced the dimerization and oligomerization of the chimeric protein leading to receptor phosphorylation and activation, thus mimicking the effect of ligand binding, whereas the wild type ALK remained as a monomeric nonphosphorylated protein. Expression of the chimera, but not that of the wild type ALK or of a kinase inactive form of the chimera, induced the differentiation of PC12 cells. Analysis of the signaling pathways involved in this process pointed to an essential role of the mitogen-activated protein kinase cascade. These results are consistent with a role for ALK in neuronal differentiation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M007333200