ALK is a novel dependence receptor: potential implications in development and cancer.

ALK (anaplastic lymphoma kinase) is a transmembrane receptor tyrosine kinase, initially discovered as part of the NPM-ALK fusion protein, resulting from a chromosomal rearrangement frequently associated with anaplastic large cell lymphomas. The native ALK protein is normally expressed in the developing and, at a weaker level, adult nervous system. We recently demonstrated that ALK is a novel dependence receptor. As such, in the absence of ligand, the ALK receptor is kinase inactive and its expression results in enhanced apoptosis, whereas kinase activation, due to a ligand or constitutive as in NPM-ALK, decreases apoptosis. Unligated/kinase unactivated ALK receptor facilitates apoptosis via its own cleavage by caspases, a phenomenon allowing the exposure of a proapoptotic juxta-membrane intra-cellular domain. This review summarizes the biological significance of the ALK receptor in cancer and development, in perspective with its dependence receptor function. The dual function of ALK in the physiology of development is illustrated in the visual system of Drosophila. In this part of the nervous system, ALK in the presence of ligand appears essential for axonal guidance, whereas in the absence of ligand, ALK expression can lead to developmental neuronal apoptosis. ALK is also found expressed in neural crest-derived tumors such as human neuroblastomas or glioblastomas but its role is not fully elucidated. However, an excessive or constitutive ALK tyrosine kinase activation can lead to deregulation of cell proliferation and survival, therefore to human cancers such as lymphomas and inflammatory myofibroblastic tumors. Our observations could have important implications in the therapy of ALK-positive tumors harboring the chimeric or wild type ALK protein.