PTPRM - Tyrosine Phosphatase Activity

Tyrosine Phosphatase Activity

There are a number of ways that RPTP catalytic activity can be regulated (for reviews, see ). Dimerization of identical RPTP proteins at the cell surface leaves the PTP domains either in an open active conformation, as in the case of PTPmu and LAR, or in an inhibited conformation that leaves the catalytic domain inaccessible, in the case of CD45, PTPalpha, and PTPzeta/beta. The binding of different parts of the protein with itself (ex. by folding to interact with itself), known as intramolecular interactions, can affect the activity of RPTPs. The cytoplasmic domains of different RPTPs can interact to yield heterodimers of RPTP proteins, which then influence catalytic activity (for example, see ).

The regulation of PTPmu catalytic activity is complex. Like most RPTPs, the membrane proximal (or D1) phosphatase domain of PTPmu is catalytically active. At high cell density, when PTPmu molecules bind to one another homophilically, phosphotyrosine levels are decreased. This suggests that PTPmu may be catalytically active at high cell density. Substrates of PTPmu (proteins that are dephosphorylated by PTPmu), such as p120catenin, tend to be dephosphorylated at high cell density, supporting the hypothesis that PTPmu is catalytically active when bound homophilically. PTPmu is constitutively dimerized due to its extracellular domain.

Crystal structure analysis of the D1 of PTPmu demonstrated that PTPmu dimers are in an open active conformation. Even though PTPmu dimers may be active, an additional study suggests that the extracellular domain of PTPmu reduces phosphatase activity. In this study, it was shown that the cytoplasmic domain of PTPmu (a PTPmu molecule lacking the extracellular domain) has greater phosphatase activity than the full-length protein in an enzymatic phosphatase assay.

PTPmu has a long juxtamembrane domain, which likely influences catalytic activity. The juxtamembrane domain of PTPmu can bind to either the D1 and/or D2 of PTPmu, but only within the same PTPmu monomer. Removal of the juxtamembrane domain from PTPmu has been suggested to reduce PTPmu phosphatase activity. The D2 domain of PTPmu also regulates its activity. Although originally demonstrated to positively regulate phosphatase activity, the D2 domain has been shown to negatively affect PTPmu catalytic activity. A wedge-shaped motif located by D1 also regulates catalytic activity. Use of a peptide with the same sequence as the wedge motif inhibits PTPmu mediated functions.

Certain stimuli may also influence PTP activity. For example, alteration of cell oxidation induces conformational changes in the cytoplasmic domain of PTPmu, which may affect its tyrosine phosphatase activity or binding of extracellular ligands.