Manipulating PTPRD function with ectodomain antibodies.

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Development

Background:

• Protein tyrosine phosphatases (PTPs) regulate signal transduction but are underexplored drug targets.
• Receptor protein tyrosine phosphatase delta (RPTPδ/PTPRD) promotes tumor progression and metastasis by increasing SRC activity.
• Receptor protein tyrosine phosphatases (RPTPs) inhibition is linked to dimerization.

Purpose of the Study:

• To develop antibodies targeting extracellular domains of RPTPδ/PTPRD to modulate dimerization and signaling.
• To investigate the therapeutic potential of targeting RPTPδ/PTPRD in cancer.

Main Methods:

• Generation of antibodies against PTPRD ectodomains.
• Validation of antibody binding to endogenous PTPRD in metastatic breast cancer cells (CAL51).
• Assessment of antibody-induced changes in phosphatase activity, dimerization, and degradation pathways (lysosomal and proteasomal).

Main Results:

• Monoclonal antibody RD-43 bound endogenous PTPRD, inhibited its phosphatase activity, and induced PTPRD degradation.
• RD-43 triggered PTPRD dimerization, impairing catalytic activity.
• Antibody-mediated PTPRD degradation occurred via lysosomal and proteasomal pathways, independent of secretase cleavage.
• RD-43 treatment inhibited SRC signaling and PTPRD-dependent cell invasion.

Conclusions:

• Targeting extracellular RPTPδ/PTPRD with antibodies can inhibit its tumor-promoting functions.
• Antibody-induced dimerization and subsequent degradation of RPTPδ/PTPRD represent a viable therapeutic strategy.
• This approach holds therapeutic potential for cancers driven by RPTPδ/PTPRD.