PTPN3: Human Protein Tyrosine Nonreceptor-type 3 (PTPH1)
PDB Code: 2B49
PTPN3 belongs to the non-receptor class of protein tyrosine phosphatses of the NT5 subtype. It contains a C-terminal PTP domain and an N-terminal domain homologous to the band 4.1 superfamily of cytoskeletal-associated proteins (FERM domain, also called ERM - for ezrin, radixin and moesin - domain) as well as a PDZ domain. PTPN3 was found to be mostly associated with membrane structures in cells and this association appears to be mediated by the N-terminal portion of PTPN3. In addition, the PTPN3 N-terminal segment has been shown to exert an inhibitory effect on its enzymatic activity in vitro
PTPN3 binds to 14-3-3 adaptor proteins in cells, in a manner dependent on phosphorylation of PTPN3 which is regulated by mitogenic signals linking tyrosine and serine/threonine phosphorylation signalling pathways. So far only a few substrates of PTPN3 have been identified: Immunoblot analysis showed that wildtype PTPN3 specifically dephosphorylates VCP (valosin-containing protein), a cell cycle regulator involved in a variety of membrane related functions. In addition, PTPN3 dephosphorylates the immune tyrosine-based activation motifs of TCR (T cell-receptor) zeta resulting in attenuation of T-cell receptor signalling. Along these lines, dephosphorylation and of the protein tyrosine kinase lck by PTPN3 results in further reduction of phosphoryaltion of the TCR.
PTPN3 is expressed in lymphoid organs but RT-PCR analysis detected high levels of PTPN3 expression in a wide variety of tumor cell lines. In addition, a study by Wang et al. showed that PTPN3 is a mutational hotspot in colorectal cancers suggesting that PTPN3 is a tumor suppressor gene regulating cellular pathways that may be amenable to therapeutic intervention.
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