Functional comparison of long and short splice forms of RPTPbeta: implications for glioblastoma treatment.
The receptor protein tyrosine phosphatase beta (RPTPbeta/PTPzeta) is overexpressed in glioblastoma tumors and plays a functional role in tumor cell migration and adhesion. Glioblastomas express at least three splice variants of RPTPbeta, including long and short receptor forms and a secreted chondroitin sulfate proteoglycan called phosphacan. Here we explore the differences in the expression pattern and function of long RPTPbeta and short RPTPbeta. The short form of RPTPbeta lacks exon 12, which encodes 860 amino acids located in the extracellular domain. Until now, functional differences between long and short RPTPbeta have been difficult to elucidate. In this study, antibodies specific to the splice junction, unique to short RPTPbeta, allowed for the discrimination of the two receptors. A study of normal brain tissue and graded astrocytomas indicates that long and short RPTPbeta forms have an overlapping expression pattern. In order to study functional differences between long and short RPTPbeta, we created stable U87 glioblastoma cells that expressed these receptors. U87 stable cell lines overexpressing long or short RPTPbeta migrate faster and adhere more robustly than parental U87 cells. The two forms differ in that long-RPTPbeta-overexpressing cells migrate and adhere better than short-RPTPbeta-overexpressing cells. A study of the extracellular domain of short RPTPbeta indicates that it retains much of the functional capacity of phosphacan. Indeed, the action of recombinant, short-RPTPbeta extracellular domain protein is similar to that of phosphacan as a repulsive substrate for glioblastoma cells. Comparison of the signaling capacity of long RPTPbeta to that of short RPTPbeta reveals very similar abilities to activate transcription pathways. Moreover, transient transfection with either long or short RPTPbeta activates NF-kappaB reporter gene transcription. Because of their tumor-restricted and largely overlapping expression patterns in glioblastoma, both RPTPbeta splice forms are potential therapeutic targets. The involvement of long and short RPTPbeta in glioma tumor cell biology also contributes to the value of RPTPbeta as a cancer target.
Lorente
Gustavo
G
AGY Therapeutics, Inc., 270 East Grand Avenue, South San Francisco, CA 94080, USA.
Nelson
April
A
Mueller
Sabine
S
Kuo
Jane
J
Urfer
Roman
R
Nikolich
Karoly
K
Foehr
Erik D
ED
D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5
D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C516895:PTPRZ1 protein, human; D017027:Protein Tyrosine Phosphatases; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5