20q13.13

Various diseases and cancers

PTP1B is involved in direct/enzymatic or indirect interactions with several proteins. In the figure, the PTPN1/PTP1B human interactome is drawn. Each protein is depicted as circle whose color refers to the human pathology where the interaction with PTP1B is found misregulated. The numbers refer to the PMID of the articles supporting the interaction data.

PTP1B as a putative tumor suppressor.
Several evidences support the notion that PTP1B is a negative regulator of cell growth, although loss of function mutations and gene silencing have not been found in human cancer. PTP1B dephosphorylates and inactivates a number of receptor protein tyrosine kinases, including the EGF (epidermal growth factor) and PDGF (platelet-derived growth factor) receptors and therefore can exert a suppressive action on growth factor cell signaling (Haj et al., 2002). Ferrari et al. have used HEK293 human embryonic kidney cell line, stimulated with a high EGF concentration and observed that overexpression of PTP1B reduces EGF-dependent ERK activation, by dephosphorylating phospho-tyrosines of the scaffold protein GAB1. These phospho-tyrosines are the docking sites of the ERK activator SHP2 phosphatase. On the contrary, inhibition of the PTP1B enzymatic activity has an opposite effect, allowing SHP2 to localize on GAB1 and exert its positive role on RAS/ERK signaling (Ferrari et al., 2010).
In 2006, Akasaki et al. proposed a molecular mechanism to explain the involvement of PTP1B in the proapoptotic effect caused by troglitazone, an anti-diabetic drug, now withdrawn by Food and Drug Administration that could represent a promising drug for adjuvant therapy of glioma and other highly migratory tumors. The troglitazone is a pharmacological agonist of the peroxisome proliferator-activated receptor-gamma (PPARgamma), that acts, in synergy with apoptosis inducing agents, to facilitate caspase signaling, in human glioma cells. Troglitazone activates PTP1B, which subsequently reduces phosphotyrosine 705 in the prosurvival protein STAT3. Reduction of pY705-STAT3 in glioma cells causes down-regulation of anti-apoptotic proteins FLIP (FLICE-inhibitory protein) and Bcl-2 (Akasaki et al., 2006; Coras et al., 2007; Lund et al., 2005).
PTP1B can also contribute to cell-cell association since it is bound to the cytoplasmic domain of N-cadherin and it is responsible for dephosphorylating phospho-tyrosine residues belonging to beta-catenin, thus maintaining the cadherin-actin connection and cell adhesion (Balsamo et al., 1998). Moreover, PTP1B is required for the trafficking of the N-cadherin precursor from the endoplasmic reticulum to the Golgi apparatus, because, by dephosphorylating the p120 catenin, it promotes the binding between N-cadherin precursor and p120 catenin, an interaction required for a correct anterograde movement (Hernández et al., 2010).

Autoimmunity and B-cell lymphomas

Lu et al. have reported a novel negative feedback loop involving the anti-tumor IL-4/Jak/STAT6 signaling and the phosphatase PTP1B, in a type of aggressive non-Hodgkin lymphoma, the activated B-cell-like diffuse large B-cell lymphomas (ABC-DLBCL). In this lymphoma, STAT6 is dephosphorylated in the nucleus and in the cytoplasm and the authors have demonstrated, by immunohistochemical analysis of 371 cases of hematolymphoid malignancies, that PTP1B is more commonly expressed in the ABC-like DLBCL. Since ABC-like DLBCL express also higher levels of TCPTP (an ubiquitous tyrosine-specific phosphatase in which the catalytic domain has 72% identity to that of PTP1B), compared with other lymphomas (GCB-like DLBCL), the authors suggested that both the phosphatases PTP1B and TCPTP regulate STAT6 signaling, by dephosphorylating STAT6 in the cytoplasm and in the nucleus, respectively. This result identifies an important regulatory loop in neoplasia, where IL-4 induces PTP1B, which suppresses IL-4 induced STAT6 signaling, and suggests that augmentation of PTP1B expression may render tumor cells insensitive to the anti-tumor effect of the IL-4/Jak/STAT6 pathway (Lu et al., 2008).

Breast cancer

PTP1b as a tumor promoter.
In clinical samples, it has been long noted that PTP1B expression increases in several human breast and ovarian cancers (Wiener et al., 1994b).
Recently, several studies have pointed out a positive role of PTP1B in oncogenic properties of breast cancer cells as well as in the sensitization or resistance of cancer cells to apoptosis induced by cytotoxic compounds. PTP1B positively regulates ErbB2-induced tumorigenesis at the level of the Ras/MAP Kinase, probably by dephosphorylating p62Dok on Tyr398, thus blocking its association with the Ras GTPase-activating protein p120 RasGAP, the Ras inhibitor (Dubé et al., 2004; Mertins et al., 2008).
PTP1B is also described as a positive regulator of human breast adenocarcinoma (MCF-7) cell line proliferation. Also in this case, PTP1B exerts a positive effect on ERK phosphorylation by a mechanism independent of the regulation of RasGAP, of the phosphorylation state of p62Dok Tyr398 or of the phosphorylation of STAT3 on Tyr705. In fact, in MCF-7 cells resistant to tamoxifen, PTP1B and the highly similar TC-PTP phosphatase are overexpressed, while ERK and STAT3 are hyperphosphorylated. This result indicates PTP1B as a new target for the treatment of tamoxifen-resistant breast cancers (Blanquart et al., 2009).
PTP1B is shown to be required for ErbB2-mediated transformation of MCF-10A human breast epithelial cells and its overexpression alters acinar morphogenesis via activation of Src. MCF-10A cells are immortalized, nontransformed cells derived from a reduction mammoplasty, which form organized acini when grown within three-dimensional matrices such as reconstituted basement membrane. In this model, transformation causes characteristic changes in acinar morphogenesis, proliferation, and luminal apoptosis, that resemble those seen in human ductal carcinoma of the breast. In MCF-10A, PTP1B expression is increased by ErbB2 and PTP1B activates the tyrosine kinase Src by dephosphorylation of its repressing tyrosine 527 (Arias-Romero et al., 2009). This result is in accordance with previous studies that analyzed frozen sections from 29 human mammary tumors and demonstrated a significant association between PTP1B overexpression and breast cancer (P < 0,038) and between the overexpression of PTP1B and the overexpression of ErbB-2 (P < 0,006) (Wiener et al., 1994b). An analogous study found a correlation between increased PTP1B overexpression, statistically associated with human ovarian carcinoma, and the expression of ErbB-2, EGFR, and CSFR growth factor receptor protein tyrosine kinases (Wiener et al., 1994a).

Susceptibility to insulin resistance and metabolic syndrome

Protein tyrosine phosphatase PTP1B negatively regulates insulin and leptin signaling. Therefore, it is considered a promising drug target for enhancing insulin sensitivity in type 2 diabetes and controlling body mass in obesity. PTP1B, in fact, dephosphorylates activating phospho-tyrosines present on the Insulin receptor molecule (INSR; OMIM 147670) in hepatocytes and myocytes, thus inhibiting insulin signaling (Ng, 2011). The activation segment within the insulin receptor contains three sites of autophosphorylation, pTyr-1158, pTyr-1162, and pTyr-1163. PTP1B exhibited a striking affinity preference for the bis- and the tris-phosphorylated peptides, with KMs of 14 and 8 μM, respectively, compared to the mono-phosphorylated peptides, where the KMs were above 100 μM, but PTP1B preferentially dephosphorylates pTyr-1162 within the tris-phosphorylated segment (Salmeen et al., 2000). When PTP1B is overexpressed, it plays a role in insulin resistance (Ahmad et al., 1997; Salmeen et al., 2000). Di Paola et al. have identified, in the 3 untranslated region of the PTP1B gene, a 1484insG variation that is associated with several features of insulin resistance and metabolic syndrome. The 1484insG allele causes PTP1B overexpression, probably by increasing PTP1B mRNA stability (Di Paola et al., 2002).
Mok et al. identified a single-nucleotide polymorphism in exon 8, designated 981CT, that could be associated with a reduced risk of diabetes since subjects with the PTP1B 981T/981C were 40% less likely to present an impaired glucose tolerance or type II diabetes (Mok et al., 2002). The PTPN1 Pro387Leu missense variant was associated with lower glucose tolerance and with a 3.7-fold increased risk of type 2 diabetes (Ukkola et al., 2005). PTPN1 IVS6+G82G homozygotes showed higher levels of all measures of adiposity. The G82A heterozygotes are potentially at higher risk for type 2 diabetes (Ukkola et al., 2005).
Obesity research is aiming at understanding and targeting the neural signaling pathways that control energy balance. The adipocyte-secreted hormone leptin acts in the brain to decrease appetite and increase energy expenditure via the simultaneous suppression of hypothalamic neurones that synthesize agouti-related protein (AgRP) and the stimulation of neurone producing proopiomelanocortin (POMC). Unfortunately, leptin cannot be used to control obesity due to the development of a resistance to leptin. PTP1B has thus became an interesting target because of its negative regulatory role on leptin signaling, mediated through a direct and selective dephosphorylation of the two main signaling molecules downstream of the activated leptin receptor, JAK2 and STAT3 (Lund et al., 2005). Moreover, interactions between the gene variants of PTPN1 and leptin receptor have been shown to contribute to the phenotypic variability of insulin sensitivity (Ukkola et al., 2005).
A recent study conducted on a sample of families with two or more members with type 2 diabetes, has revealed an association of common PTPN1 SNPs and haplotypes with coronary artery calcification (CorCP), which is a surrogate measure of atherosclerosis and subclinical cardiovascular disease. The authors observed that PTPN1 haplotype GACTTCAGO, associated with type 2 diabetes, was also significantly associated with increased CorCP (Burdon et al., 2006). The Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort study has investigated the possible role of common genetic variations in PTPN1 on the development of hypertension, hyperlipidemia and obesity. The study has analyzed common (> 2%) sequence variation of PTPN1 in Japanese and Chinese descent, in order to study the association of individual SNPs and resulting haplotypes with quantitative phenotypes characteristic of the metabolic syndrome (Olivier et al., 2004). Because of the regulating properties of PTP1B, efforts are made to produce small molecules able to target the active site of the phosphatase in order to treat diabetes. Recently Haque et al. have isolated a single chain variable fragment antibody that stabilizes the inactive form of PTP1B thereby inhibiting its catalytic activity. This small molecule could inspire development of inhibitors that stabilize the inactive conformation of PTP1B (Haque et al., 2011).