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Molecular and Cellular Biology, August 2006, p. 6209-6222, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.01515-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Anaplastic Lymphoma Kinase Is a Dependence Receptor Whose Proapoptotic Functions Are Activated by Caspase Cleavage

Jaouhar Mourali,1,{dagger} Alan Bénard,1,{dagger} Filipe Calheiros Lourenço,2 Céline Monnet,1 Catherine Greenland,1 Christel Moog-Lutz,3 Claire Racaud-Sultan,1 Daniel Gonzalez-Dunia,1 Marc Vigny,3 Patrick Mehlen,2 Georges Delsol,1 and Michèle Allouche1*

INSERM U563, CPTP, CHU Purpan, BP 3028, 31024 Toulouse Cedex 3, France,1 Apoptosis, Cancer and Development Laboratory, Equipe labellisée "La Ligue," CNRS FRE2870, Centre Léon Bérard, Lyon, France,2 INSERM U706, UPMC, IFM, 17 rue du Fer à Moulin, Paris, France3

Received 5 August 2005/ Returned for modification 4 October 2005/ Accepted 5 June 2006

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.

* Corresponding author. Mailing address: INSERM U563, CPTP, CHU Purpan, BP3028, 31024 Toulouse Cedex 3, France. Phone: 33-5 62 74 45 29. Fax: 33-5 62 74 45 58. E-mail: allouche{at}toulouse.inserm.fr.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, August 2006, p. 6209-6222, Vol. 26, No. 16
0270-7306/06/$08.00+0     doi:10.1128/MCB.01515-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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