Disease relevance of PTPN13

• This 4q21.3 chromosomal region contains a gene for autosomal dominant polycystic kidney disease as well as the region frequently deleted in liver and ovarian cancers, suggesting that PTPN13 is a candidate for one of the putative tumor suppressor genes on the long arm of chromosome 4 [1].
• Protein-tyrosine phosphatase PTPL1/FAP-1 triggers apoptosis in human breast cancer cells [2].
• Based on the FAP-1- and dynamin-dependent regulation of Fas translocation, we have created human melanoma lines with different levels of surface expression of Fas [3].
• The structure also reveals that four out of five PTPL1 mutations found in colorectal cancers are located on solvent-exposed regions remote from the active site, consistent with these mutants being normally active [4].
• FAP-1 in pancreatic cancer cells: functional and mechanistic studies on its inhibitory role in CD95-mediated apoptosis [5].

High impact information on PTPN13

• A protein tyrosine phosphatase, FAP-1, capable of interacting with the cytosolic domain of Fas, was identified [6].
• The variant TTR is not present in the serum of 100 normal individuals, in four cases of primary and six cases of secondary amyloidosis, nor in 26 non-inheriting members of families with FAP1 [7].
• Amyloid fibrils isolated from type I FAP (FAP1) of Portuguese, Swedish, and Japanese origins consist of a variant transthyretin (TTR) that contains a methionine-for-valine substitution at position 30 or a mixture of normal TTR and this variant form [7].
• Forced expression of FAP-1 reduces cell surface Fas levels and increases the intracellular pool of Fas within the cytoskeleton network [8].
• FasL, Fas, FADD, RIP, caspase-8, caspase-3, Bid, FLIP(S+L), FLASH and FAP-1, proteins known to act within the Fas-apoptosis cascade, showed no changes in their expression levels in cells treated with butyrate compared with untreated cells [9].

Chemical compound and disease context of PTPN13

• Crystal structure of the PTPL1/FAP-1 human tyrosine phosphatase mutated in colorectal cancer: evidence for a second phosphotyrosine substrate recognition pocket [4].
• Conserved serine-rich motifs identified in the repeat units of P120 and P140 were also found in the repeat units of the human granulocytotropic ehrlichiosis agent 130-kDa protein and of the fimbria-associated adhesin protein Fap1 of Streptococcus parasanguis [10].

Biological context of PTPN13

• The localization of the PTPN13 gene to human chromosome 4q21.3 was determined by both FISH and PCR analysis of somatic cell hybrids [1].
• Studies in Jurkat leukemia cells have suggested that protein-tyrosine phosphatase PTPL1/FAP-1 rescues Fas-induced cell death [2].
• PTP-BAS may thus play a regulatory role in activation of NF-kappaB under high oxidative stress [11].
• PTPN13, a fas-associated protein tyrosine phosphatase, is located on the long arm of chromosome 4 at band q21.3 [1].
• Toward this end, we prepared synthetic proteins with either the catalytic domain of FAP-1 (C-terminal 399 amino acids) or its inactive form (Cys2408-->Ser) fused to glutathione-S-transferase (GST) [12].

Anatomical context of PTPN13

• Using TIG3 normal human fibroblasts and human melanoma cell lines, we investigated transcriptional regulation of FAP-1, a regulator of Fas translocation in the cell [3].
• Human tumor cell lines become resistant to Fas-mediated apoptosis when transfected with FAP-1, indicating that FAP-1 functions as a negative regulator in Fas-mediated death signaling [12].
• Following stimulation of cells with hydrogen peroxide to induce PtdIns(3,4) P (2) production, PTPL1, complexed to TAPP1, translocates to the plasma membrane [13].
• Using confocal laser scanning microscopy we show that in Panc89 cells FAP-1 is mainly associated with the Golgi complex and with peripheral vesicles [5].
• After RT-PCR cloning of PTPs expressed in MCF 7 cells with primers to their catalytic domains, we have shown, by differential screening, that the expression of two enzymes, leukocyte common antigen-related PTP (LAR) and Fas-associated PTP-1 (FAP-1), was modulated by antiestrogens [14].

Associations of PTPN13 with chemical compounds

• We use the second PDZ domain (PDZ2) of the human protein tyrosine phosphatase (hPTP1E) as a model to study the energetics of peptide binding to a class I PDZ domain [15].
• In particular, we demonstrate that a conserved C-terminal cysteine of PRK2 is indispensable for the interaction with PTP-BL [16].
• Interestingly, a positively charged pocket is located near the PTPL1 catalytic site, reminiscent of the second phosphotyrosine binding site in PTP1B, which is required to dephosphorylate peptides containing two adjacent phosphotyrosine residues (as occurs for example in the activated insulin receptor) [4].
• Both the carboxyl group and side chain of the valine residue at the C terminus of Fas are essential, and the leucine and serine residues in the 2nd and 3rd positions, respectively, from the C terminus are important for the interactions with PDZ 2 and PDZ 4 of PTPL1 [17].
• In addition, hPTP1E contains five imperfect repeats possessing significant homology to the GLGF repeats of the junction-associated guanylate kinases such as the Drosophila discs-large tumor suppressor gene (dlg-1) [18].

Physical interactions of PTPN13

• TRIP6 also interacts with the second out of five PDZ motifs in PTP-BL [19].
• Interaction of the protein tyrosine phosphatase PTPL1 with the PtdIns(3,4)P2-binding adaptor protein TAPP1 [13].
• The solution structure of the second PDZ domain from human phosphatase hPTP1E in complex with a C-terminal peptide from the guanine nucleotide exchange factor RA-GEF-2 has been determined using 2D and 3D heteronuclear NMR experiments [20].

Enzymatic interactions of PTPN13

• Using an in vitro dephosphorylation reaction, we found that FAP-1 dephosphorylates IkappaBalpha [12].
• FAP-1 dephosphorylates phospho-tyrosine 275 in the carboxyl terminus of FAS [21].
• We first show by complementary approaches that PTPL1 specifically dephosphorylates insulin receptor substrate-1 (IRS-1) in vitro and in cellulo [22].

Regulatory relationships of PTPN13

• FAP-1 displayed enhanced colocalization with CD95 upon CD95 stimulation in the Golgi complex but not in surface-associated vesicles [5].
• Protein tyrosine phosphatase L1 (PTPL1) was identified as a gene upregulated by EWS-FLI1 in transfected cells by microarray [23].
• Because apoptosis is a common mechanism leading to neuronal death in neurodegenerative disorders, the authors investigated the immunohistochemical distribution of FAP-1 in the hippocampus of elderly control subjects and Alzheimer disease (AD) patients [24].
• These results imply that the FAP-1 gene may be a target gene under the control of important apoptosis-related nuclear factors in human cancers [25].

Other interactions of PTPN13

• These results provide the first evidence that PTPL1/FAP-1 has a key role in the apoptotic process in human breast cancer cells independent of Fas but associated with an early inhibition of the insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway [2].
• Taken together, PTP-BL, RIL and TRIP6 may function as components of multi-protein complexes at actin-based sub-cellular structures [19].
• RNA expression analysis revealed overlapping patterns of expression for TRIP6, RIL and PTP-BL, most notably in tissues of epithelial origin [19].
• Head-to-head juxtaposition of Fas-associated phosphatase-1 (FAP-1) and c-Jun NH2-terminal kinase 3 (JNK3) genes: genomic structure and seven polymorphisms of the FAP-1 gene [26].
• Both Fas ligand and Fas-associated phosphatase-1 (FAP-1) were expressed only in COLO320DM [27].

Analytical, diagnostic and therapeutic context of PTPN13

• The specific interaction of this novel protein with the second PDZ domain of hPTP1E was demonstrated both in vitro, using bacterially expressed proteins, and in vivo, by co-immunoprecipitation studies [28].
• Using these clones as a probe, PTPN13 was assigned to human chromosome region 4q21 and mouse chromosome region 5E/F by fluorescence in situ hybridization (FISH) [29].
• Furthermore, levels of FAP-1 protein also correlated with the amounts of FAP-1 mRNA, as determined by reverse transcriptase-polymerase chain reaction analysis [30].
• FAP-1 protein levels were investigated by immunoblotting in the National Cancer Institute's panel of 60 human tumor cell lines [30].
• These antibodies were used for immunoblotting, immunohistochemistry, and flow-cytometry analysis of FAP-1 expression in the Fas-sensitive ovarian cancer lines HEY and BG-1, and in the Fas-resistant lines OVCAR-3 FR and SK-OV-3 [30].

References