© 2005 by the Society forNeuro-Oncology
Functional comparison of long and short splice forms of RPTPβ:Implications for glioblastoma treatment
AGY Therapeutics, Inc., 270 East Grand Avenue, South San Francisco,CA 94080, USA
1 Address correspondence to Erik D. Foehr, AGY Therapeutics, Inc., 270 EastGrand Avenue, South San Francisco, CA 94080, USA(efoehr{at}agyinc.com).
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Abstract |
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The receptor protein tyrosine phosphatase beta (RPTPβ PTP
) isoverexpressed in glioblastoma tumors and plays a functional role in tumor cellmigration and adhesion. Glioblastomas express at least three splice variantsof RPTPβ, including long and short receptor forms and a secretedchondroitin sulfate proteoglycan called phosphacan. Here we explore thedifferences in the expression pattern and function of long RPTPβ andshort RPTPβ. The short form of RPTPβ lacks exon 12, which encodes860 amino acids located in the extracellular domain. Until now, functionaldifferences between long and short RPTPβ have been difficult toelucidate. In this study, antibodies specific to the splice junction, uniqueto short RPTPβ, allowed for the discrimination of the two receptors. Astudy of normal brain tissue and graded astrocytomas indicates that long andshort RPTPβ forms have an overlapping expression pattern. In order tostudy functional differences between long and short RPTPβ, we createdstable U87 glioblastoma cells that expressed these receptors. U87 stable celllines overexpressing long or short RPTPβ migrate faster and adhere morerobustly than parental U87 cells. The two forms differ in thatlong-RPTPβ-overexpressing cells migrate and adhere better thanshort-RPTPβ-overexpressing cells. A study of the extracellular domain ofshort RPTPβ indicates that it retains much of the functional capacity ofphosphacan. Indeed, the action of recombinant, short-RPTPβ extracellulardomain protein is similar to that of phosphacan as a repulsive substrate forglioblastoma cells. Comparison of the signaling capacity of long RPTPβ tothat of short RPTPβ reveals very similar abilities to activatetranscription pathways. Moreover, transient transfection with either long orshort RPTPβ activates NF-
B reporter gene transcription. Because oftheir tumor-restricted and largely overlapping expression patterns inglioblastoma, both RPTPβ splice forms are potential therapeutic targets.The involvement of long and short RPTPβ in glioma tumor cell biology alsocontributes to the value of RPTPβ as a cancer target.
Received May 27, 2004; Accepted November 2, 2004