PTPN1 (protein tyrosine phosphatase, non-receptor type 1)

2012-01-01   Giuseppe Leuzzi , Alberto Calderone , Luisa Castagnoli 

Department of Biology, University of Rome Tor Vergata, Rome, Italy





PTPN1 is located at 49126891-49201299 bp; chromosome 20, strand +, Unigene cluster Hs.417549, Entrez gene Id 57570.
The gene is located in a genomic region that has been identified in multiple linkage studies as a QTL for obesity and diabetes (Ghosh et al., 1999; Soro et al., 2002).


In humans, PTPN1, the gene coding for PTP-1B, is located on human chromosome 20q13. The 10 exons of the gene span more than 74 kb of genomic DNA, in the centromere-to-telomere orientation. The promoter region of PTPN1 gene contains no TATA box, but multiple GC rich sequences in which a number of consensus SP-1 binding sites are present (Forsell et al., 2000).


The open reading frame includes 1305 bp and codes for a protein of 435 amino acids (Olivier et al., 2004).
According to Ensembl, PTPN1 gene has two alternative transcripts:
- PTPN1-001: 10 exons, 3529 bp mRNA, 435 amino acids;
- PTPN1-201: 9 exons, 1634 bp mRNA, 362 amino acids.
(Ensembl database: Ensembl Reference Sequence: ENST00000371621 (PTPN1-001), ENST00000541713 (PTPN1-201)).


No human pseudogene for PTPN1 has been identified.



Size: 435 amino acids; 49967 Da.


PTP1B is expressed abundantly.


Endoplasmic reticulum membrane; peripheral membrane protein; cytoplasmic side.


Belongs to the protein-tyrosine phosphatase family. Non-receptor class 1 subfamily; IUBMB enzyme nomenclature: EC
PTP1B (P18031 in UniProtKB) has an N-terminal catalytic phosphatase domain (residues 1-300) followed by a regulatory region of about 80-100 residues and a membrane localization domain (residues 400-435) that tethers the enzyme to the cytoplasmic face of the endoplasmic reticulum (ER). The enzymatic activity is tightly controlled by means of four described mechanisms: oxidation, phosphorylation, SUMOylation, and proteolysis. PTP1B activity is regulated in vivo by reversible oxidation involving Cys 215 at its active site and SUMOylation at two lysines (i.e., 335 and 347). Serine or tyrosine phosphorylation can affect protein interactions (Yip et al., 2010).



The 1484insG variation (OMIM variation (176885.0001)) (Meshkani et al., 2007), the single-nucleotide polymorphism (SNP) 981CT (Mok et al., 2002), VS6+G82A polymorphism, G82G, Pro387Leu variant (Ukkola et al., 2005).

Implicated in

Entity name
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.
Atlas Image
The PTP1B human interactome. Interactions are categorized according to OLS (The Ontology Lookup Service) and according to evidence collected in the major PPI databases (Protein-Protein Interaction Databases). Interactions indicated with dashed lines are enzymatic reaction. Interactions indicated with continuous lines are interactions related to methodologies like: two hybrid, protein complementation assay, affinity chromatography technology and similar methodologies that imply a physical interaction. According to Mentha - the Interactome browser.
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).
Entity name
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).
Entity name
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).
Entity name
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).


Pubmed IDLast YearTitleAuthors
93227961997Improved sensitivity to insulin in obese subjects following weight loss is accompanied by reduced protein-tyrosine phosphatases in adipose tissue.Ahmad F et al
163190702006A peroxisome proliferator-activated receptor-gamma agonist, troglitazone, facilitates caspase-8 and -9 activities by increasing the enzymatic activity of protein-tyrosine phosphatase-1B on human glioma cells.Akasaki Y et al
194359112009Activation of Src by protein tyrosine phosphatase 1B Is required for ErbB2 transformation of human breast epithelial cells.Arias-Romero LE et al
97869601998The nonreceptor protein tyrosine phosphatase PTP1B binds to the cytoplasmic domain of N-cadherin and regulates the cadherin-actin linkage.Balsamo J et al
196354552009Implication of protein tyrosine phosphatase 1B in MCF-7 cell proliferation and resistance to 4-OH tamoxifen.Blanquart C et al
165052272006Association of protein tyrosine phosphatase-N1 polymorphisms with coronary calcified plaque in the Diabetes Heart Study.Burdon KP et al
175410352007The peroxisome proliferator-activated receptor-gamma agonist troglitazone inhibits transforming growth factor-beta-mediated glioma cell migration and brain invasion.Coras R et al
118330062002A variation in 3' UTR of hPTP1B increases specific gene expression and associates with insulin resistance.Di Paola R et al
147669792004The role of protein tyrosine phosphatase 1B in Ras signaling.Dubé N et al
211231822011Identification of new substrates of the protein-tyrosine phosphatase PTP1B by Bayesian integration of proteome evidence.Ferrari E et al
111373002000Genomic characterization of the human and mouse protein tyrosine phosphatase-1B genes.Forsell PA et al
100516181999Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs.Ghosh S et al
118728382002Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum.Haj FG et al
219625152011Conformation-sensing antibodies stabilize the oxidized form of PTP1B and inhibit its phosphatase activity.Haque A et al
201818252010The protein tyrosine phosphatase PTP1B is required for efficient delivery of N-cadherin to the cell surface.Hernández MV et al
187161322008PTP1B is a negative regulator of interleukin 4-induced STAT6 signaling.Lu X et al
158211012005Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling.Lund IK et al
185158602008Investigation of protein-tyrosine phosphatase 1B function by quantitative proteomics.Mertins P et al
1756046320071484insG polymorphism of the PTPN1 gene is associated with insulin resistance in an Iranian population.Meshkani R et al
118363112002A single nucleotide polymorphism in protein tyrosine phosphatase PTP-1B is associated with protection from diabetes or impaired glucose tolerance in Oji-Cree.Mok A et al
216238612011Regulation of glucose metabolism and the skeleton.Ng KW et al
152291882004Single nucleotide polymorphisms in protein tyrosine phosphatase 1beta (PTPN1) are associated with essential hypertension and obesity.Olivier M et al
111632132000Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B.Salmeen A et al
118916172002Genome scans provide evidence for low-HDL-C loci on chromosomes 8q23, 16q24.1-24.2, and 20q13.11 in Finnish families.Soro A et al
159198352005Protein tyrosine phosphatase 1B variant associated with fat distribution and insulin metabolism.Ukkola O et al
81662061994Overexpression of the tyrosine phosphatase PTP1B is associated with human ovarian carcinomas.Wiener JR et al
79059281994Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression.Wiener JR et al
203813582010PTP1B: a double agent in metabolism and oncogenesis.Yip SC et al

Other Information

Locus ID:

NCBI: 5770
MIM: 176885
HGNC: 9642
Ensembl: ENSG00000196396


dbSNP: 5770
ClinVar: 5770
TCGA: ENSG00000196396


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Adherens junctionKEGGko04520
Insulin signaling pathwayKEGGko04910
Adherens junctionKEGGhsa04520
Insulin signaling pathwayKEGGhsa04910
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Interferon SignalingREACTOMER-HSA-913531
Interferon alpha/beta signalingREACTOMER-HSA-909733
Regulation of IFNA signalingREACTOMER-HSA-912694
Interferon gamma signalingREACTOMER-HSA-877300
Regulation of IFNG signalingREACTOMER-HSA-877312
Growth hormone receptor signalingREACTOMER-HSA-982772
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
Platelet Aggregation (Plug Formation)REACTOMER-HSA-76009
Integrin alphaIIb beta3 signalingREACTOMER-HSA-354192
Signal TransductionREACTOMER-HSA-162582
Insulin resistanceKEGGhsa04931
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 Down-RegulationREACTOMER-HSA-8849472
Signaling by METREACTOMER-HSA-6806834
Negative regulation of MET activityREACTOMER-HSA-6807004

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
221694772011H2S-Induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response.144
201189222010Membrane contacts between endosomes and ER provide sites for PTP1B-epidermal growth factor receptor interaction.114
231762562013Protein tyrosine phosphatases--from housekeeping enzymes to master regulators of signal transduction.112
152585702004Allosteric inhibition of protein tyrosine phosphatase 1B.107
206826872010Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program.88
183322192008Calpain 2 and PTP1B function in a novel pathway with Src to regulate invadopodia dynamics and breast cancer cell invasion.76
188406082008Cysteine S-nitrosylation protects protein-tyrosine phosphatase 1B against oxidation-induced permanent inactivation.64
170566362007Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations.59
179749542007PTP1B contributes to the oncogenic properties of colon cancer cells through Src activation.49
197827702010The two faces of PTP1B in cancer.49


Giuseppe Leuzzi ; Alberto Calderone ; Luisa Castagnoli

PTPN1 (protein tyrosine phosphatase, non-receptor type 1)

Atlas Genet Cytogenet Oncol Haematol. 2012-01-01

Online version: