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J. Biol. Chem., Vol. 280, Issue 29, 26953-26964, July 22, 2005

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Differential Induction of Glioblastoma Migration and Growth by Two Forms of Pleiotrophin^*

Kan V. Lu, Kimberly A. Jong, Gloria Y. Kim, Jatinder Singh, Ederlyn Q. Dia, Koji Yoshimoto, Maria Y. Wang¶, Timothy F. Cloughesy||**, Stanley F. Nelson**, and Paul S. Mischel**

From the Departments of Pathology and Laboratory Medicine, ^||Neurology, and Human Genetics and ^**Henry E. Singleton Brain Tumor Program, David Geffen School of Medicine, University of California, Los Angeles, California 90095

Glioblastoma is the most common malignant brain tumor of adults and one of the most lethal cancers. The secreted growth factor pleiotrophin (PTN) promotes glioblastoma migration and proliferation, initiating its oncogenic activities through two cell surface receptors, the protein tyrosine phosphatase receptor (PTPRZ1) and the anaplastic lymphoma kinase (ALK), respectively. Here, we report on the presence and purification of two naturally occurring forms of PTN (18 and 15 kDa) that differentially promote glioblastoma migration and proliferation. Using a panel of glioblastoma cell lines, including low passage patient-derived cultures, we demonstrate that PTN15 promotes glioblastoma proliferation in an ALK-dependent fashion, whereas immobilized PTN18 promotes haptotactic migration of glioblastoma cells in a PTPRZ1-dependent fashion. Mass spectrometric analysis indicated that PTN15 differs from PTN18 by processing of 12 C-terminal amino acids. To demonstrate clinical relevance, we show that PTN15, PTN18, and PTPRZ1 are significantly overexpressed in glioblastoma relative to normal brain at both mRNA and protein levels using microarray, Western blot, and tissue microarray analyses on human tumors. These results indicate that the PTN18-PTPRZ1 and the PTN15-ALK signaling pathways represent potentially important therapeutic targets for glioblastoma invasion and growth.

Received for publication, March 9, 2005 , and in revised form, May 16, 2005.

^* This work was supported in part by NINDS Grants NS050151 and NS43147 from the National Institutes of Health (to P. S. M.) and an Accelerate Brain Cancer Cure Award (to P. S. M.). This work was also supported by the Harry Allgauer Foundation through The Doris R. Ullmann Fund for Brain Tumor Research Technologies, a Henry E. Singleton Brain Tumor Fellowship (to P. S. M.), and a generous donation from the Ziering Family Foundation in memory of Sigi Ziering. 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.

Supported by UCLA Tumor Cell Biology Training Grant 5T32CA09056 funded by the National Cancer Institute.

^¶ Supported by a Translational Research Grant from American Brain Tumor Association and a Seed Grant from UCLA Jonsson Cancer Center Foundation.

To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave., Los Angeles, CA 90095-1732. Tel.: 310-794-5223; Fax: 310-206-8290; E-mail: pmischel{at}mednet.ucla.edu.

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