PTPN14: Human Protein tyrosine Phosphatases 14 (PEZ, PTP36)
PDB Code: 2BZL
PTPN14 (Pez) is a member of the cytoplamic FERM-domain containing protein tyrosine phosphatase (PTP) family which are characterized by a FERM (Band 4.1, ezrin, radixin, moesin homology) domains at their N-termini, and PTP (protein tyrosine phosphatase) domains at their C-termini. PTPN14 was first cloned in a screen for PTPs expressed in normal breast tissue. It is also expressed in varying amounts in other tissues including kidney, skeletal muscle, lung and placenta. In addition, PTPN14 is highly expressed in human umbilical vein endothelial cells (HUVEC), suggesting it may be a critical enzyme in regulating endothelial cell function.
PTPN14 belongs to the NT6 subtype of PTPs. Its FERM domain directs PTPN14 to the cytoskeleton/plasma membrane interface in a phosphoinositide-dependent manner. PTPN14 also contains an acidic region and a putative SH3 domain-binding sequence in the region between the ezrin-like and catalytic domain. Conservation of the FERM superfamily PTP in Caenorhabditis elegans but not in yeast suggests a fundamental role in the multi-cellular organism.
Subcellular localization of PTPN14 is regulated in both HeLa and human umbilical vein endothelial cells (HUVEC). In cells grown to confluence PTPN14 is localized in the cytosol, where it is concentrated at intercellular junctions, but it is predominantly nuclear in sparsely plated cells that have not yet formed extensive cell-cell contacts. Other factors also regulate the subcellular localization of PTPN14, including TGFβ , which inhibits translocation of PTPN14 from the cytosol to the nucleus. Furthermore, PTPN14 has been detected in the nucleus in migrating and proliferative cells at the wound edge. TGFβ, which is known to inhibit cell proliferation but not migration, inhibits translocation of PTPN14 to the nucleus, further strengthening the argument that PTPN14 plays a role in the nucleus during cell proliferation.
Knockout mice of PTPN14 show uterine dilation and the presence of keratin in the uterine lumen. Homozygous mutant females have no or reduced mammary gland tissue and an increased anogenital distance.
Mutation in the PTPN14 gene may also play a role in cancer cell invasion and metastasis since increased phosphorylation of adherens junctions has been shown to increase cell motility and migration. β-catenin, a central molecule in adherence junction and in the wnt-signaling cascade, has been identified as a PTPN14 substrate. In addition, dominant negative PTPN14 enhances both tyrosine phosphorylation of adherens junctions and cell motility. Because increased phosphorylation of adherens junctions has been shown to increase cell motility and migration, mutational inactivation of these genes may be an important step in cancer cell invasion and metastasis. This notion is supported by a mutational analysis of the tyrosine phosphatase gene superfamily in human cancers which identified somatic mutations in PTPN14, affecting together 26% of colorectal cancers and a smaller fraction of lung, breast, and gastric cancers. Many mutations identified were nonsense, frameshift, or splice site alterations predicted to result in truncated proteins lacking phosphatase activity, suggesting that the mutated tyrosine phosphatases like PTPN14 are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention.
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