Receptor protein tyrosine phosphatases (RPTPs) are type I transmembrane proteins with intracellular tyrosine phosphatase domains linked to cell adhesion molecule (CAM)-like extracellular domains. Numerous studies demonstrate that RPTPs regulate cell-cell adhesion, cell-extracellular matrix adhesion and/or cell migration, similar to other CAMs. In the context of cancer biology this is significant, as the dissolution of stable cell-cell and increased cell-matrix adhesions have been documented as essential early steps in tumor progression. Eight RPTP subfamilies have been identified, each with distinct extracellular domain structures [1
]. In the context of tumorigenesis, four RPTP subfamilies have been strongly implicated: the LAR Type IIa, the PTPμ Type IIb, the PTPα Type IV, and the PTPζ/β Type V subfamilies.
The extracellular domain structure of RPTPs, as with CAMs in general, determines the ligands they interact with in their environment. For example, some RPTPs bind to identical ligands, known as homophilic binding. Other RPTPs bind to different ligands, known as heterophilic binding. Depending on whether the ligands are present on other cells or in the extracellular matrix, RPTPs are able to promote either cell-cell adhesion or cell-extracellular matrix adhesion. The Type IIa, IIb, and V RPTP families mediate distinct types of cell adhesion. Type IIa RPTPs, PTPδ, PTPσ, and LAR, mediate heterophilic cell-cell adhesion with netrin-G-ligand 3 (NGL-3), heparin sulfate proteoglycans or the Laminin/nidogen complex [4
]. However, PTPδ and specific isoforms of LAR can also mediate homophilic binding [8
]. Adhesion mediated by this family has been reviewed [10
]. The type IIb PTPμ-like subfamily of RPTPs, including PTPμ, PTPρ, PTPκ, and PCP-2 (PTPλ), mediate homophilic cell-cell adhesion [11
], with the exception of PCP-2 [17
]. The adhesion mediated by this subfamily has been reviewed in [3
]. Finally, the type V PTPζ/β family, including PTPζ (RPTPβ) and PTPγ, mediates heterophilic cell-matrix adhesion via the interaction with a number of different molecules, including with neural cell adhesion molecule (NCAM), the extracellular matrix protein, tenascin, and the neurite outgrowth promoting molecule, pleiotrophin [20
Mis-expression and mutation of various RPTPs has been linked to tumorigenesis [25
]. Recent data demonstrates that cleavage of the extracellular domain (ECD) and intracellular domain (ICD) of RPTPs regulates RPTP function and may be significant in cancer progression [26
]. ECD cleavage observed for RPTPs is similar to the well-documented Notch cleavage paradigm, in which three proteases sequentially digest Notch to release biologically active protein fragments [27
RPTP cleavage can have a number of effects. First, because they function as adhesion molecules, shedding of the RPTP’s ECD would dramatically change cell-cell and cell-matrix adhesion, likely promoting migration over adhesion. Second, release of the catalytic tyrosine phosphatase domains of cleaved RPTPs from the plasma membrane will likely impact signaling mediated by RPTPs. Evidence for this exists, as most of the RPTP ICDs translocate to the nucleus [28
]. Finally, we suggest that the phosphatase activity of the membrane-based RPTP will differ from its nuclear-fragment, as has been described for PTPα and PTPε [32
]. This is likely not only due to changes in substrate availability in the different subcellular compartments, but also due to conformational changes in the tyrosine phosphatase domains that can affect their activity (see [19
] for review of regulation of RPTP catalytic activity).
The best evidence exists for cleavage of type IIb RPTPs in cancer progression. Although there is evidence for the cleavage of three other RPTP subfamilies, the connection between cleavage of these RPTPs and cancer is not as clear. In general, full-length RPTPs are speculated to function as tumor suppressors [25
]. We postulate that cleaved RPTP fragments function as oncogenes [26
]. The full length tumor suppressor versus cleaved oncogene hypothesis may explain the conflicting reports on the role of RPTPs in cancer. Cleavage of RPTPs may be preferentially triggered in cancer cells as a consequence of increased protease expression during cancer progression [34
] or increased RPTP glycosylation [35
]. In this review, we will summarize what is currently known about the cleavage of four RPTP subfamilies and their link to cancer progression. Finally, we will conclude with a discussion of how we can exploit the presence of cleaved RPTP fragments to develop cancer molecular diagnostic tests and molecular imaging agents.