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J. Biol. Chem., Vol. 280, Issue 28, 26039-26048, July 15, 2005

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Activation and Inhibition of Anaplastic Lymphoma Kinase Receptor Tyrosine Kinase by Monoclonal Antibodies and Absence of Agonist Activity of Pleiotrophin^*

Christel Moog-Lutz, Joffrey Degoutin, Jean Y. Gouzi, Yvelyne Frobert¶, Nicole Brunet-de Carvalho, Jocelyne Bureau, Christophe Créminon¶, and Marc Vigny||

From the INSERM, Unité 706/Université Pierre et Marie Curie, Paris F-75005 and the ^¶Service de Pharmacologie et d'Immunologie, Direction de la Recherche Médicale, Commissariat à l'Energie Atomique-Saclay, Gif/Yvette 91191, France

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is transiently expressed in specific regions of the central and peripheral nervous systems, suggesting a role in its normal development and function. The nature of the cognate ligands of ALK in vertebrate is still a matter of debate. We produced a panel of monoclonal antibodies (mAbs) directed against the extracellular domain of the human receptor. Two major species of ALK (220 and 140 kDa) were identified in transfected cells, and the use of our mAbs established that the 140-kDa species results from a cleavage of the 220-kDa form. Two mAbs, in the nM range, induced the differentiation of PC12 cells transiently transfected with ALK. In human embryonic kidney 293 cells stably expressing ALK, these two mAbs strongly activated the receptor and subsequently the mitogen-activated protein kinase pathway. We further showed for the first time that activation of ALK also resulted in a specific activation of STAT3. In contrast, other mAbs presented the characteristics of blocking antibodies. Finally, in these cell systems, a mitogenic form of pleiotrophin, a proposed ligand of ALK, failed to activate this receptor. Thus, in the absence of clearly established ligand(s) in vertebrates, the availability of mAbs allowing the activation or the inhibition of the receptor will be essential for a better understanding of the biological roles of ALK.

Received for publication, February 22, 2005 , and in revised form, May 6, 2005.

^* This work was supported in part by institutional funding from INSERM and Université Paris 6 as well as by grants from the Association pour la Recherche sur le Cancer and the Association Française contre les Myopathies. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed: INSERM Unité 706/UPMC, Institut du Fer à Moulin, 17 rue du Fer à Moulin, Paris F-75005, France. E-mail: vigny{at}fer-a-moulin.inserm.fr.

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