title: Anaplastic lymphoma kinase is a dependence receptor whose proapoptotic functions are activated by caspase cleavage.
abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, initially discovered as part of the NPM-ALK fusion protein, resulting from the t(2;5) translocation that is 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 the oncogenic, constitutively kinase-activated NPM-ALK protein was antiapoptotic when expressed in Jurkat lymphoblastic cells treated with cytotoxic drugs. In contrast, we now show that Jurkat cells overexpressing the wild-type ALK receptor are more sensitive to doxorubicin-induced apoptosis than parental cells. Moreover, the ALK protein is cleaved during apoptosis in a caspase-dependent manner. Mutation of aspartic residues to asparagine allowed us to map the caspase cleavage site in the juxtamembrane region of ALK. In order to assess the role of ALK in neural cell-derived tissue, we transiently expressed ALK in the 13.S.1.24 rat neuroblast immortalized cell line. ALK expression led to apoptotic cell death of the neuroblasts. ALK ligation by specific activating antibodies decreased ALK-facilitated apoptosis in both lymphoid and neuronal cell lines. Moreover, ALK transfection reduced the survival of primary cultures of cortical neurons. Thus, ALK has a proapoptotic activity in the absence of ligand, whereas it is antiapoptotic in the presence of its ligand and when the kinase is intrinsically activated. These properties place ALK in the growing family of dependence receptors.
authors.affiliation: INSERM U563, CPTP, CHU Purpan, BP3028, 31024 Toulouse Cedex 3, France.
authors.forename: Jaouhar
authors.initials: J
authors.lastname: Mourali
authors.forename: Alan
authors.initials: A
authors.lastname: Bénard
authors.forename: Filipe Calheiros
authors.initials: FC
authors.lastname: Lourenço
authors.forename: Céline
authors.initials: C
authors.lastname: Monnet
authors.forename: Catherine
authors.initials: C
authors.lastname: Greenland
authors.forename: Christel
authors.initials: C
authors.lastname: Moog-Lutz
authors.forename: Claire
authors.initials: C
authors.lastname: Racaud-Sultan
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez-Dunia
authors.forename: Marc
authors.initials: M
authors.lastname: Vigny
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
authors.forename: Georges
authors.initials: G
authors.lastname: Delsol
authors.forename: Michèle
authors.initials: M
authors.lastname: Allouche
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D001224:Aspartic Acid / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014162:Transfection
chemical_list: D000906:Antibodies; D011956:Receptors, Cell Surface; D001224:Aspartic Acid; D004317:Doxorubicin; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases