A novel splice variant of the protein tyrosine phosphatasePTPRJthat encodes for a soluble protein involved in angiogenesis

Abstract

PTPRJ is a receptor protein tyrosine phosphatase with tumor suppressor activity. Very little is known about the role of PTPRJ ectodomain, although recently both physiological and synthetic PTPRJ ligands have been identified. A putative shorter spliced variant, coding for a 539 aa protein corresponding to the extracellular N-terminus of PTPRJ, is reported in several databases but, currently, no further information is available.Here, we confirmed that the PTPRJ short isoform (named sPTPRJ) is a soluble protein secreted into the supernatant of both endothelial and tumor cells. Like PTPRJ, also sPTPRJ undergoes post-translational modifications such as glycosylation, as assessed by sPTPRJ immunoprecipitation. To characterize its functional activity, we performed an endothelial cell tube formation assay and a wound healing assay on HUVEC cells overexpressing sPTPRJ and we found that sPTPRJ has a proangiogenic activity. We also showed that sPTPRJ expression down-regulates endothelial adhesion molecules, that is a hallmark of proangiogenic activity. Moreover, sPTPRJ mRNA levels in human high-grade glioma, one of the most angiogenic tumors, are higher in tumor samples compared to controls. Further studies will be helpful not only to clarify the way sPTPRJ works but also to supply clues to circumvent its activity in cancer therapy.

The receptor protein tyrosine phosphatase PTPRJ negatively modulates the CD98hc oncoprotein in lung cancer cells

“…To examine cell migration, 3.5 × 10 5 A549 cells were seeded in a 6-well plate; the following day, cells were transfected with 100 pmol of CD98hc siRNA and infected with Ad PTPRJ at MOI50; twenty-four hours later, cell layer in the dishes was scratched using 200 μl plastic pipette tips as previously described [ 59 ]. The closure of wounded area was measured six, twenty-four and forty-eight hours later by using a motorized inverted fluorescent microscope coupled with an high-sensitivity EM-CCD camera (Leica).…”

Analysis of Receptor-Type Protein Tyrosine Phosphatase Extracellular Regions with Insights from AlphaFold

“…Various splice variants have been described for this subgroup of RPTPs. Alternative splicing of the PTPRJ gene produces a soluble form of CD148 (sPTPRJ) lacking the transmembrane domain and intracellular phosphatase domain [30], although the functional significance of this protein is unclear. Splicing of the PTPRO gene produces a truncated isoform (PTPROt) that lacks the extracellular domain but has a transmembrane domain and intracellular phosphatase domain that is identical with full-length PTPRO.…”

Role of Protein Phosphatases in Tumor Angiogenesis: Assessing PP1, PP2A, PP2B and PTPs Activity

“…However, significantly higher upregulation of PTPRJ has been identified in glioblastoma multiforme, indicating a potentially cancerspecific function of PTPRJ [249,250]. PTPRJ plays a negative role in regulating EC growth by inhibiting VEGF-dependent ERK1/2 activation [251,252]. Upon VEGF stimulation, PTPRJ dephosphorylates and a enuates VEGFR-2 activity, resulting in the subsequent downregulation of the proliferative PLCγ-ERK1/2 signaling cascade [251,252].…”

“…PTPRJ plays a negative role in regulating EC growth by inhibiting VEGF-dependent ERK1/2 activation [251,252]. Upon VEGF stimulation, PTPRJ dephosphorylates and a enuates VEGFR-2 activity, resulting in the subsequent downregulation of the proliferative PLCγ-ERK1/2 signaling cascade [251,252]. Furthermore, VE-cadherin inhibits VEGFR-2 proliferative signaling by binding and retaining VEGFR-2 at the cell surface, thereby preventing its endocytosis and favoring its inactivation by PTPRJ [5].…”

“…Several studies have confirmed PTPRJ-mediated Src activation. PTPRJ dephosphorylates the inhibitory Tyr residue of Src, leading to Src auto-phosphorylation and full activation, which can initiate tumor-associated angiogenesis [250][251][252]254]. A short variant of PTPRJ, named sPTPRJ, is generated by alternative splicing, resulting in a soluble protein secreted into the supernatant by both endothelial and tumor cells.…”