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 tyrosi ne kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems, suggesting a role in its no rmal development and function. To determine whether ALK could play a role i n neuronal differentiation, we established a model system that allowed us t o 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 dimerizat ion and oligomerization of the chimeric protein leading to receptor phospho rylation and activation, thus mimicking the effect of ligand binding, where as the wild type ALK remained as a monomeric nonphosphorylated protein. Exp ression of the chimera, but not that of the wild type ALK or of a kinase in active form of the chimera, induced the differentiation of PC12 cells. Anal ysis of the signaling pathways involved in this process pointed to an essen tial role of the mitogen-activated protein kinase cascade. These results ar e consistent with a role for ALK in neuronal differentiation.