|
|
|
|
|
|
||
|
|
||||
|
|
||||
|
||||
Tumor Biology |
AGY Therapeutics, Inc., 270 East Grand Avenue, South San Francisco, CA 94080, USA
1 Address correspondence to Erik D. Foehr, AGY Therapeutics, Inc., 270 East Grand Avenue, South San Francisco, CA 94080, USA (efoehr{at}agyinc.com).
Abstract
The receptor protein tyrosine phosphatase beta (RPTPß PTP
) is
overexpressed in glioblastoma tumors and plays a functional role in tumor cell
migration and adhesion. Glioblastomas express at least three splice variants
of RPTPß, 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 RPTPß and
short RPTPß. The short form of RPTPß lacks exon 12, which encodes
860 amino acids located in the extracellular domain. Until now, functional
differences between long and short RPTPß have been difficult to
elucidate. In this study, antibodies specific to the splice junction, unique
to short RPTPß, allowed for the discrimination of the two receptors. A
study of normal brain tissue and graded astrocytomas indicates that long and
short RPTPß forms have an overlapping expression pattern. In order to
study functional differences between long and short RPTPß, we created
stable U87 glioblastoma cells that expressed these receptors. U87 stable cell
lines overexpressing long or short RPTPß migrate faster and adhere more
robustly than parental U87 cells. The two forms differ in that
long-RPTPß-overexpressing cells migrate and adhere better than
short-RPTPß-overexpressing cells. A study of the extracellular domain of
short RPTPß indicates that it retains much of the functional capacity of
phosphacan. Indeed, the action of recombinant, short-RPTPß extracellular
domain protein is similar to that of phosphacan as a repulsive substrate for
glioblastoma cells. Comparison of the signaling capacity of long RPTPß to
that of short RPTPß reveals very similar abilities to activate
transcription pathways. Moreover, transient transfection with either long or
short RPTPß activates NF-
B reporter gene transcription. Because of
their tumor-restricted and largely overlapping expression patterns in
glioblastoma, both RPTPß splice forms are potential therapeutic targets.
The involvement of long and short RPTPß in glioma tumor cell biology also
contributes to the value of RPTPß as a cancer target.
|
|
