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J. Biol. Chem., Vol. 282, Issue 39, 28683-28690, September 28, 2007

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Anaplastic Lymphoma Kinase Is Activated Through the Pleiotrophin/Receptor Protein-tyrosine Phosphatase / Signaling Pathway

AN ALTERNATIVE MECHANISM OF RECEPTOR TYROSINE KINASE ACTIVATION^*

Pablo Perez-Pinera¹², Wei Zhang¹³, Yunchao Chang³, Jose Antonio Vega, and Thomas F. Deuel⁴

From the Scripps Research Institute, La Jolla, California 92037 and Universidad San Pablo-CEU, Madrid, Spain

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) first discovered as the constitutively active nucleophosmin-ALK oncoprotein in anaplastic large cell lymphomas (ALCL). Full-length ALK has a critical role in normal development and differentiation. Activated full-length ALK also is found in different malignant cancers. Nevertheless, the ligand to activate ALK remained unknown until recently, when ALK was proposed to be the physiological receptor of the cytokine pleiotrophin (PTN, Ptn). However, earlier studies had demonstrated that receptor protein tyrosine phosphatase (RPTP) / is a physiological PTN receptor. We now demonstrate that phosphorylation of ALK in PTN-stimulated cells is mediated through the PTN/RPTP/ signaling pathway. ALK is phosphorylated independently of a direct interaction of PTN with ALK. The data thus support a unique model of ALK activation. In cells not stimulated by PTN, RPTP/ dephosphorylates ALK at the site(s) in ALK that is undergoing autophosphorylation through autoactivation. In contrast, when RPTP/ is inactivated in PTN-stimulated cells, the sites that are autophosphorylated in ALK no longer can be dephosphorylated by RPTP/; thus, autoactivation and tyrosine phosphorylation of ALK rapidly increase. The data indicate that the PTN/RPTP/ signaling pathway is a critical regulator of the steady state levels of tyrosine phosphorylation and activation of ALK; the data support the conclusion that ALK phosphorylation and activation in PTN-stimulated cells are increased through a unique "alternative mechanism of RTK activation."

Received for publication, June 1, 2007 , and in revised form, August 2, 2007.

^* This work was supported by National Institutes of Health Grant CA84400. The Molecular and Experimental Medicine core laboratory is supported by the Sam and Rose Stein Endowment Fund. This is manuscript number 18518 from the Scripps Research Institute. 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.

¹ These authors contributed equally to this work.

² Supported by Grant 2 T32 DK007022-26 from the National Institutes of Health.

³ Supported by a Skaggs training grant.

⁴ To whom correspondence should be addressed: The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-7923; Fax: 858-784-7977; E-mail: tfdeuel{at}scripps.edu.

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