Alternative titles; symbols
HGNC Approved Gene Symbol: PTPN1
Cytogenetic location: 20q13.13 Genomic coordinates (GRCh38): 20:50,510,383-50,585,241 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.13 | {Insulin resistance, susceptibility to} | 125853 | Autosomal dominant | 3 |
The phosphorylation of proteins at tyrosine is an important regulatory component in signal transduction, neoplastic transformation, and the control of the mitotic cycle. As in systems regulated by serine or threonine phosphorylation, the phosphorylation of proteins at tyrosine is reversible. The reaction is catalyzed by protein-tyrosine phosphatases (PTPases; protein-tyrosine phosphate phosphohydrolase; EC 3.1.3.48). These enzymes appear to be highly specific for phosphotyrosyl proteins and bear little resemblance to either the protein-serine phosphatases or protein-threonine phosphatases or the acid and alkaline phosphatases. Tonks et al. (1988) and Charbonneau et al. (1989) purified a form of this enzyme, PTP1B, from human placenta and determined its amino acid sequence. The protein sequence was found to be unrelated to those of other known phosphatases but similar to the common leukocyte antigen (CD45; 151460) and to LAR (179590).
Chernoff et al. (1990) cloned cDNA for PTP1B. The sequence predicted that the protein contains an additional 114 amino acids not present in the reported peptide sequence.
Brown-Shimer et al. (1990) isolated a cDNA clone for PTP1B. The translation deduced from the 1,305-nucleotide open reading frame predicted a protein containing 435 amino acids and having a molecular mass of 49,966 Da. The N-terminal 321 amino acids deduced from the cDNA sequence were identical to the empirically determined sequence reported by Charbonneau et al. (1989).
PTP1B is the founding member (Tonks et al., 1988) of a family of more than 40 PTPases, including receptor-like transmembrane forms and cytosolic enzymes, that are characterized by homologous catalytic domains of approximately 240 amino acids.
Fukada and Tonks (2003) found that overexpression of Yb1 (NSEP1; 154030) in Rat1 cells resulted in increased Ptp1b expression. Depletion of Yb1 decreased Ptp1b expression, increased sensitivity to insulin, and enhanced signaling through the cytokine receptor gp130 (IL6ST; 600694), which was suppressed by reexpression of Ptp1b. Fukada and Tonks (2003) also found a correlation between expression of PTP1B and YB1 in several human cancer cell lines and in an animal model of type II diabetes (125853). They concluded that YB1 is an important regulator of PTP1B expression.
In order to test whether PTP1B is spatially regulated, Yudushkin et al. (2007) developed a method based on Forster resonant energy transfer for imaging enzyme-substrate intermediates in live cells. Yudushkin et al. (2007) observed the establishment of a steady-state enzyme-substrate gradient across the cell. This gradient exhibited robustness to cell-to-cell variability, growth factor activation, and receptor tyrosine kinase localization, which demonstrated spatial regulation of PTP1B activity. Yudushkin et al. (2007) postulated that such regulation may be important for generating distinct cellular environments that permit receptor tyrosine kinase signal transduction and mediate its eventual termination.
To provide insight into the structural basis of substrate recognition by PTP1B, Jia et al. (1995) determined the structures of a catalytically inactive cys215-to-ser mutant form of the enzyme complexed with high-affinity peptide substrates corresponding to an autophosphorylation site of the epidermal growth factor receptor (131550).
The protein-tyrosine phosphatase PTP1B is responsible for negatively regulating insulin (176730) signaling by dephosphorylating the phosphotyrosine (ptyr) residues of the insulin receptor (INSR; 147670) kinase activation segment, or IRK. By integrating crystallographic, kinetic, and PTP1B peptide-binding studies, Salmeen et al. (2000) defined the molecular specificity of this reaction. Extensive interactions are formed between PTP1B and the IRK sequence encompassing the tandem ptyr residues at positions 1162 and 1163, such that ptyr1162 is selected at the catalytic site and ptyr1163 is located within an adjacent ptyr-recognition site. This selectivity is attributed to the 70-fold greater affinity for tandem ptyr-containing peptides relative to mono-ptyr peptides and predicts a hierarchical dephosphorylation process. Many elements of the PTP1B-IRK interaction are unique to PTP1B, indicating that it may be feasible to generate specific, small molecule inhibitors of this interaction to treat diabetes and obesity.
Haj et al. (2002) used fluorescence resonance energy transfer (FRET) methods to monitor interactions between the epidermal- and platelet-derived growth factor (173410) receptors and PTP1B. PTP1B-catalyzed dephosphorylation required endocytosis of the receptors and occurred at specific sites on the surface of the endoplasmic reticulum. Most of the receptor tyrosine kinases (RTKs) activated at the cell surface showed interaction with PTP1B after internalization, establishing that RTK activation and inactivation are spatially and temporally partitioned within cells.
Salmeen et al. (2003) described a structural analysis of the redox-dependent regulation of PTP1B, which is reversibly inhibited by oxidation after cells are stimulated with insulin and epidermal growth factor (131530). The sulfenic acid intermediate produced in response to PTP1B oxidation is rapidly converted into a theretofore unknown sulfenyl-amide species, in which the sulfur atom of the catalytic cysteine is covalently linked to the main chain nitrogen of an adjacent residue. Oxidation of PTP1B to the sulfenyl-amide form is accompanied by large conformational changes in the catalytic site that inhibit substrate binding. Salmeen et al. (2003) proposed that this unusual protein modification both protects the active-site cysteine residue of PTP1B from irreversible oxidation to sulfonic acid and permits redox regulation of the enzyme by promoting its reversible reduction by thiols.
Van Montfort et al. (2003) reported the crystal structures of the regulatory sulfenic and irreversible sulfinic and sulfonic acids of PTP1B. They also identified a sulfenyl-amide species that is formed through oxidation of its catalytic cysteine. Formation of the sulfenyl-amide causes large changes in the PTP1B active site, which are reversible by reduction with the cellular reducing agent glutathione. The sulfenyl-amide is a protective intermediate in the oxidative inhibition of PTP1B. In addition, it may facilitate reactivation of PTP1B by biologic thiols and signal a unique state of the protein.
Forsell et al. (2000) cloned and determined the genomic organization for both the human and mouse PTPN1 genes, including the promoter. The human gene spans more than 74 kb and has a large first intron of more than 54 kb; the mouse gene likewise contains a large first intron, although the exact size was not determined. The organization of the human and mouse PTPN1 genes is identical except for an additional exon at the 3-prime end of the human gene that is absent in the mouse.
Fukada and Tonks (2003) determined that the promoter region of the PTPN1 gene lacks a TATA box, but it contains a p210 BCR-ABL (see 151410)-responsive sequence that contains binding sites for the transcription factors EGR1 (128990), SP1 (189906), and SP3 (601804). PTPN1 also contains a functional YB1 element.
Brown-Shimer et al. (1990) isolated a genomic clone and used it in nonisotopic in situ hybridization to banded metaphase chromosomes to determine that the PTPN1 gene is present in single copy on 20q13.1-q13.2.
By FISH, Forsell et al. (2000) mapped the mouse Ptpn1 gene to distal chromosome 2 in the region H2-H3. This region is associated with a mouse obesity quantitative trait locus (QTL) and shows conserved synteny with human chromosome 20.
PTP1B inhibits insulin signaling and, when overexpressed, plays a role in insulin resistance (Ahmad et al., 1997). In the 3-prime untranslated region of the PTP1B gene, Di Paola et al. (2002) identified a 1484insG variation (176885.0001) that, in 2 different populations, was associated with several features of insulin resistance (see 125853). Similar data were obtained in a family-based association study by use of sib pairs discordant for genotype (Gu et al., 2000). Subjects carrying the 1484insG variant showed PTP1B mRNA overexpression in skeletal muscle. PTP1B mRNA stability was significantly higher in human embryonic kidney cells transfected with 1484insG PTP1B as compared with those transfected with wildtype PTP1B. The data indicated that the 1484insG allele causes PTP1B overexpression and plays a role in insulin resistance. Therefore, individuals carrying the 1484insG variant might particularly benefit from PTP1B inhibitors in the treatment of insulin resistance (Kennedy and Ramachandran, 2000).
Mok et al. (2002) identified a novel single-nucleotide polymorphism (SNP), designated 981CT. They found a significant association between this SNP and the risk of either impaired glucose tolerance (IGT) or type II diabetes in the Oji-Cree of Sandy Lake, Ontario, Canada. They genotyped 653 subjects using PCR amplification of exon 8, followed by digestion with the restriction enzyme AvaI. Sixty-eight subjects were heterozygotes, and none was a homozygote. Thus, the overall frequencies of the C allele and the T allele were 0.948 and 0.052, respectively. Subjects with the PTP1B 981T/981C genotype were approximately 40% less likely to have IGT or diabetes as subjects with the 981C/981C genotype (P = 0.040). There was no difference in quantitative traits among subjects grouped according to the PTP1B 981CT genotype. The authors concluded that genomic variation in PTP1B could be associated with a reduced risk of diabetes.
Olivier et al. (2004) genotyped 1,553 individuals from 672 Chinese and Japanese families at 6 SNPs in the PTPN1 gene and found strong association of common risk haplotypes with hypertension (p less than 0.0001). In addition, individual SNPs showed association with total plasma cholesterol, LDL-cholesterol, and VLDL-cholesterol levels, as well as with obesity measures (body mass index). Olivier et al. (2004) concluded that PTPN1 may affect plasma lipid levels and lead to obesity and hypertension in Japanese and Chinese. They further suggested that the gene may play a role in the development of the so-called metabolic syndrome (605552).
Ukkola et al. (2005) studied the impact of SNPs in the PTPN1 gene on body fat distribution and insulin metabolism in 502 white and 276 black individuals. White individuals with the GG genotype at the IVS6+82G-A SNP had significantly higher percentages of body fat, sums of 8 skinfold measurements, and highest amounts of subcutaneous fat on the extremities than those with AA or AG genotypes; however, the trunk-to-extremity skinfold ratio, adjusted for age, sex, and fat mass, was lower in GG than AA or AG individuals. White AG heterozygotes showed the lowest acute insulin response to glucose, an index of insulin secretion, even after adjustment for age, sex and fat mass, suggesting some degree of beta cell dysfunction. Ukkola et al. (2005) observed significant interaction effects between PTPN1 and the leptin receptor gln223-to-arg polymorphism (Q223R; 601007.0001) on glucose metabolism-related indices in whites.
Elchebly et al. (1999) generated PTP1B-deficient mice by targeted disruption of the mouse homolog of the PTP1B gene. Mice were phenotypically and pathologically normal and had normal life span. In the fed state, homozygous mutant mice had slightly lower blood glucose concentrations, and half the circulating insulin concentrations, of wildtype littermates. The enhanced insulin sensitivity of PTP1B-deficient mice was also evident in glucose- and insulin-tolerance tests. After insulin injection, deficient mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue compared to wildtype mice. On a high-fat diet, Ptp1b-deficient mice were resistant to weight gain and remained insulin sensitive, while wildtype mice rapidly gained weight and became insulin resistant. These results suggested a major role for PTP1B in modulation of insulin sensitivity and fuel metabolism. The authors proposed PTP1B as a potential therapeutic target for the treatment of type II diabetes and obesity.
Klaman et al. (2000) found that Ptp1b-deficient mice had low adiposity and were protected from diet-induced obesity. Decreased adiposity was due to a reduction in fat cell mass without a decrease in adipocyte number. Leanness in Ptp1b-deficient mice was accompanied by increased basal metabolic rate and total energy expenditure without marked alteration of uncoupling protein (UCP1; 113730) mRNA expression. In addition, insulin-stimulated whole-body glucose disposal was enhanced significantly in Ptp1b-deficient animals. Increased insulin sensitivity was tissue specific, as insulin-stimulated glucose uptake was elevated in skeletal muscle, whereas adipose tissue was unaffected.
Zabolotny et al. (2002) and Cheng et al. (2002) found that Ptp1b regulates leptin (164160) signaling in mice. Ptp1b was expressed in hypothalamic regions harboring leptin-responsive neurons. Ptp1b dephosphorylated the leptin receptor (601007)-associated kinase Jak2 (147796). Compared with wildtype littermates, Ptp1b-null mice had decreased leptin/body fat ratios, leptin hypersensitivity, and enhanced leptin-induced hypothalamic Stat3 (102582) phosphorylation. Zabolotny et al. (2002) found that gold thioglucose treatment, which ablates leptin-responsive hypothalamic neurons, partially reversed resistance to obesity in Ptp1b-null mice.
Bence et al. (2006) generated tissue-specific Ptpn1 -/- mice and found that neuronal knockout mice had reduced weight and adiposity, and increased activity and energy expenditure. In contrast, adipose Ptpn -/- mice had increased body weight, and Ptpn1 deletion in muscle or liver did not affect weight. The neuronal Ptpn1 -/- mice were hypersensitive to leptin, despite paradoxically elevated leptin levels, and showed improved glucose homeostasis. Bence et al. (2006) concluded that PTPN1 regulates body mass and adiposity primarily through actions in the brain, and that neuronal PTPN1 regulates adipocyte leptin production and is likely essential for the development of leptin resistance.
Heinonen et al. (2006) found that, in the presence of myeloid growth factors, bone marrow (BM) from Ptp1b -/- mice differentiated into monocytic colonies in a larger proportion than did BM from wildtype mice. The major cytokine implicated in Ptp1b -/- BM differentiation was Csf1 (120420), as Ptp1b -/- and wildtype BM showed no difference in the number of monocytes produced in response to Gmscf (CSF2; 138960) or in the number of granulocytes produced in response to Gcsf (CSF3; 138970). Csf1-treated Ptp1b -/- BM underwent more frequent cell division than wildtype BM not because of increased Csf1r (164770) expression, but because of increased Csf1r tyr807 phosphorylation. In vivo, young adult Ptp1b -/- mice had expanded monocytic and granulocytic populations compared with older mice due to reduced apoptosis. Ptp1b -/- cells also displayed increased inflammatory activity in vitro and in vivo through constitutive upregulation of activation markers and increased sensitivity to endotoxin. Heinonen et al. (2006) concluded that PTP1B is an important modulator of myeloid differentiation and macrophage activation and that PTP1B has a role in immune regulation.
Julien et al. (2007) investigated the role of PTP1B in mammary tumorigenesis using both genetic and pharmacologic approaches. It had been shown that transgenic mice with a deletion mutation in the region of ErbB2 (164870) encoding its extracellular domain developed mammary tumors that progressed to lung metastasis (Siegel et al., 1994). However, Julien et al. (2007) showed that deletion of PTP1B activity in these transgenic mice either by breeding with Ptpn1-deficient mice or by treatment with a specific PTP1B inhibitor resulted in significant mammary tumor latency and resistance to lung metastasis. In contrast, specific overexpression of PTP1B in mammary gland led to spontaneous breast cancer development. The regulation of ErbB2-induced mammary tumorigenesis by PTP1B occurs through the attenuation of both the map kinase (MAPK1; 176948) and AKT (AKT1; 164730) pathways. Julien et al. (2007) concluded that these findings provided a rationale for the development of PTP1B as a therapeutic target in breast cancer.
In the 3-prime UTR of the PTPN1 gene, Di Paola et al. (2002) identified a 1-bp insertion, 1484G, that, in 2 different populations, was associated with several features of insulin resistance (see 125853).
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