Protein tyrosine phosphatases (PTPs) are critical regulators of signal transduction but have yet to be exploited fully for drug development. Receptor protein tyrosine phosphatase δ (RPTPδ/PTPRD) has been shown to elicit tumor-promoting functions, including elevating SRC activity and promoting metastasis in certain cell contexts. Dimerization has been implicated in the inhibition of receptor protein tyrosine phosphatases (RPTPs). We have generated antibodies targeting PTPRD ectodomains with the goal of manipulating their dimerization status ectopically, thereby regulating intracellular signaling. We have validated antibody binding to endogenous PTPRD in a metastatic breast cancer cell line, CAL51, and demonstrated that a monoclonal antibody, RD-43, inhibited phosphatase activity and induced the degradation of PTPRD. Similar effects were observed following chemically induced dimerization of its phosphatase domain. Mechanistically, RD-43 triggered the formation of PTPRD dimers in which the phosphatase activity was impaired. Subsequently, the mAb–PTPRD dimer complex was degraded through lysosomal and proteasomal pathways, independently of secretase cleavage. Consequently, treatment with RD-43 inhibited SRC signaling and suppressed PTPRD-dependent cell invasion. Together, these findings demonstrate that manipulating RPTP function via antibodies to the extracellular segments has therapeutic potential.

中文翻译：

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使用胞外域抗体操纵 PTPRD 功能

蛋白酪氨酸磷酸酶 (PTP) 是信号转导的关键调节因子，但尚未充分用于药物开发。受体蛋白酪氨酸磷酸酶 δ (RPTPδ/PTPRD) 已被证明能够引发肿瘤促进功能，包括提高 SRC 活性并促进某些细胞环境中的转移。二聚化与受体蛋白酪氨酸磷酸酶 (RPTP) 的抑制有关。我们已经生成了针对 PTPRD 胞外域的抗体，目的是异位操纵其二聚化状态，从而调节细胞内信号传导。我们在转移性乳腺癌细胞系 CAL51 中验证了抗体与内源性 PTPRD 的结合，并证明单克隆抗体 RD-43 可以抑制磷酸酶活性并诱导 PTPRD 降解。在化学诱导其磷酸酶结构域二聚化后观察到类似的效果。从机制上讲，RD-43 引发 PTPRD 二聚体的形成，其中磷酸酶活性受损。随后，mAb-PTPRD 二聚体复合物通过溶酶体和蛋白酶体途径降解，与分泌酶裂解无关。因此，用 RD-43 治疗可抑制 SRC 信号传导并抑制 PTPRD 依赖性细胞侵袭。总之，这些发现表明，通过细胞外片段抗体操纵 RPTP 功能具有治疗潜力。