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Angiogenesis, Metastasis, and the Cellular Microenvironment

Tumor-Derived Extracellular Mutations of PTPRT/PTP Are Defective in Cell Adhesion

¹ Case Comprehensive Cancer Center and Departments of ² Genetics, ³ Molecular Biology and Microbiology, and ⁴ Neurosciences, School of Medicine, Case Western Reserve University; and ⁵ Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio

Requests for reprints: Zhenghe Wang, Department of Genetics and Case Comprehensive Cancer Center, Case Western Reserve University, Wolstein Research Building 3-120, 10900 Euclid Avenue, Cleveland, OH 44106. Phone: 216-368-0446; Fax: 216-368-8919. E-mail: zhenghe.wang{at}case.edu

Receptor protein tyrosine phosphatase T (PTPRT/PTP) 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 PTP. However, the functional significance of those extracellular domain mutations remains to be defined. Here we report that the extracellular domain of PTP mediates homophilic cell-cell aggregation. This homophilic interaction is very specific because PTP 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 PTP 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)