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Receptor protein tyrosine phosphatases (RPTPs) have cell adhesion molecule–like extracellular domains coupled to cytoplasmic tyrosine phosphatase domains. PTPμ is the prototypical member of the type IIb subfamily of RPTPs, which includes PTPρ, PTPκ, and PCP-2. The authors performed the first comprehensive analysis of the subfamily in one system, examining adhesion and antibody recognition. The authors evaluated if antibodies that they developed to detect PTPmu also recognized other subfamily members. Notably, each antibody recognizes distinct subsets of type IIb RPTPs. PTPμ, PTPρ, and PTPκ have all been shown to mediate cell-cell aggregation, and prior work with PCP-2 indicated that it can mediate bead aggregation in vitro. This study reveals that PCP-2 is unique among the type IIb RPTPs in that it does not mediate cell-cell aggregation via homophilic binding. The authors conclude from these experiments that PCP-2 is likely to have a distinct biological function other than cell-cell aggregation.

The receptor protein tyrosine phosphatase T PTPrho is the most frequently mutated tyrosine phosphatase in human cancer. PTPrho mediates homophilic cell-cell aggregation. In its extracellular region, PTPrho has cell adhesion molecule-like motifs, including a MAM domain, an immunoglobulin domain, and four fibronectin type III (FNIII) repeats. Tumor-derived mutations have been identified in all of these extracellular domains. Previously, the authors determined that tumor-derived mutations in the MAM and immunoglobulin domains of PTPrho reduce homophilic cell-cell aggregation. In this paper, the authors describe experiments in which the contribution of the FNIII repeats to PTPrho-mediated cell-cell adhesion was evaluated. The results demonstrate that deletion of the FNIII repeats of PTPrho result in defective cell-cell aggregation. Furthermore, all of the tumor-derived mutations in the FNIII repeats of PTPrho also disrupt cell-cell aggregation. These results further support the hypothesis that mutational inactivation of PTPrho may lead to cancer progression by disrupting cell-cell adhesion.

Receptor protein tyrosine phosphatase T (PTPRT/PTPρ) is frequently mutated in human cancers including colon, lung, gastric, and skin cancers. More than half of the identified tumor-derived mutations are located in the extracellular part of PTPρ. However, the functional significance of those extracellular domain mutations remains to be defined. Here we report that the extracellular domain of PTPρ mediates homophilic cell-cell aggregation. This homophilic interaction is very specific because PTPρ does not interact with its closest homologue, PTPμ, in a cell aggregation assay. We further showed that all five tumor-derived mutations located in the NH2-terminal MAM and immunoglobulin domains impair, to varying extents, their ability to form cell aggregates, indicating that those mutations are loss-of-function mutations. Our results suggest that PTPρ may play an important role in cell-cell adhesion and that mutational inactivation of this phosphatase could promote tumor migration and metastasis. (Mol Cancer Res 2008;6(7):1106–13)