PTPN6 (protein tyrosine phosphatase, non-receptor type 6)

2012-11-01   Alessandro Beghini , Francesca Lazzaroni 

Department of Medical Biotechnology, Translational Medicine, Universita degli Studi di Milano, Milano, Italy

Identity

HGNC
LOCUSID
ALIAS
HCP,HCPH,HPTP1C,PTP-1C,SH-PTP1,SHP-1,SHP-1L,SHP1
FUSION GENES

DNA/RNA

Atlas Image
Schematic representation of the human PTPN6 gene. Adapted from Wu et al., 2003.

Description

The human PTPN6 gene is divided in 17 exons spanning a length of 14740 bp. A notable feature of the PTPN6 gene is that it has two promoter regions. Whereas the distal promoter, P1, located upstream of the very short exon 1 (also known as exon 1a) is active in epithelial cells, the proximal promoter P2 that initiates gene transcription from exon 2 (known as exon 1b), is utilized by the hematopoietic cells. The function of P1 promoter has been partially elucidated, while the structure and regulatory mechanism of the P2 promoter remain essentially unknown.
Recent findings, characterized the hematopoietic cell-specific P2 promoter of PTPN6 gene as well as identified the PU.1 transcription factor as the activator of the P2 promoter.

Transcription

There are three transcript variants:
The variant 1 represents the predominant variant and encodes the shortest isoform.
The variant 2 originates by an alternate 5 terminal exon compared to transcript variant 1, resulting in an isoform (2) with a distinct and longer (by 2 aa) N-terminus, compared to isoform 1.
The variant 3 uses an alternate 5 terminal exon, and an alternate acceptor splice site at the penultimate exon, compared to transcript variant 1, resulting in a longer isoform (3, also known as 70 kDa SHP-1L protein) with distinct N and C termini, compared to isoform 1.

Proteins

Description

PTPN6 contain two adjacent NH2 - terminal SH2 domains, two tandem Src homology (SH2) domains, a catalytic domain, and a -COOH terminal tail of 100 amino-acid residues.

Expression

PTPN6 tyrosine phosphatase is encoded by the PTPN6 gene and expressed primarily in the hematopoietic and epithelial cells.
Atlas Image
Crystal structure of human protein tyrosine phosphatase SHP-1. The blue region represents the N-terminal of protein, while the red region represents the C-terminal of protein.

Function

PTPN6 plays a peculiar role in the maturation and functional differentiation of lymphoid and myeloid cells as underlined by the aberrant proliferation and impaired hematopoiesis in the "motheaten" (me) mice that display defects in the Shp-1 gene expression. The role of PTPN6 in hematopoiesis has been shown in motheaten and viable motheaten (meν) mice, characterized by mutations at the Shp-1 locus. The Shp-1 mRNA from me bone marrow cells have a 101 bp frameshift deletion in the coding region of the N-terminal SH2 domain, while meν bone marrow cells have an in-frame 15 bp deletion or a 69 bp in-frame insertion within the PTPase catalytic domain. Shp-1 acts in the immune and other hematopoietic cells by inhibiting signaling through receptors for cytokines, growth factors and chemokines as well as receptors involved in the immune responses and programmed cell death. Moreover, PTPN6 acts as tumor suppressor and loss of its expression has been identified in the whole spectrum of myeloid and lymphoid malignancies.
According to Gilfillan, PTPN6 is found to be constitutively associated with FcεRI, with an opponing roles in FcεRI-mediated mast cell signaling. The study demonstrated that PTPN6 caused the decreased phosphorylation of FcεRI and Syk, but, also, an enhanced phosphorylation of JNK and an increased of the TNF production is observed. This study, suggests that PTPN6 may play a negative role proximal to FcεRI.
It was also demonstrated that the PTPN6 protein tyrosine phosphatase negatively modulates the glucose homeostasis and insulin activity, through a dephosphorylation of transmembrane glycoprotein Carcinoembryonic Antigen-related Cell Adhesion Molecule-1 (CEACAM-1).
The data obtained from in vitro studies, suggested that the deficiency of PTPN6 was associated with the increase in insulin-evoked tyrosin phosphorylation of the insulin receptor, IRS-1 and IRS-2, as well as enhanced activation of PI3K and Akt in liver and skeletal muscle.
Moreover, the activation of PTPN6, through a PKC-δ and p38α MAPK actions on PDGFRβ is involved in hyperglycemia and causes an increase vascular cell apoptosis and diabetic vascular complications.

Mutations

Note

The absence or impaired function of PTPN6 in the homozygous state causes the development of the motheaten phenotype in mice, an autosomal recessive condition with focal skin inflammation and the absence of hair. Failure of neutrophils to undergo apoptosis results in the accumulation of these cells in the peripheral blood, skin, lung and spleen of affected mice.

Somatic

A pathologically similar extensive skin infiltration by neutrophils is present in Pyoderma gangrenosum (PG) and Sweets syndrome (SW), two uncommon neutrophilic dermatoses of unknown origin. Isoforms resulting from deletions of exons 2, 5, 11, and 15 and retention of intron 1 or 5 were identified in a patients with a familial case of SW, who had a neonatal onset of an inflammatory disorder with skin lesions and a biopsy specimen consistent with SW. These isoforms were associated with a heterozygous E441G mutation and a heterozygous 1,7-kbp deletion in the promoter region of the PTPN6 gene. The E441G mutation changes the hydrophilic, negatively charged amino acid glutamate to the hydrophobic nonpolar, aliphatic amino acid glycine, thereby potentially affecting the tertiary structure of PTPN6. SW an acute febrile neutrophilic dermatoses appears in several clinical forms as idiopathic, tumor associated, postinfectious and drug induced (for example after an administration of granulocyte macrophage colony stimulating factor). SW and PG have strong associations with hematological tumors. Recent studies have shown that patient with leukemia and lymphoma had methylated a P2 promoter in the PTPN6 gene, causing the absence of PTPN6 protein.
PTPN6 is expressed at low level in non-hematopoietic cells while higher levels of this protein are found in hematopoietic precursors. PTPN6 promoter methylation causes loss of expression in leukemias, which results in the activation of the JAK/STAT pathway. PTPN6 plays a role in chronic myelogenous leukemia transformation and progression: it seems to be physically associated with BCR-ABL being able both to block BCR-ABL-dependent transformation and to mediate PP2A induced BCR-ABL proteosome-degradation. The tyrosine phosphatase PTPN6 plays a prominent role as resistance determinant of Imatinib (IMA) treatment response in Chronic Myelogenous Leukemia cell lines (sensitive/KCL22-S and resistant/KCL22-R).
The lack of PTPN6 expression is frequent in malignant T cells and results from methylation of the PTPN6 gene promoter. Loss of PTPN6 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK + anaplastic large-cell lymphoma.
According to Wus research, in most human Burkitts lymphoma cell lines, the expression of SHP-1 is decreased suggesting a role of SHP-1 in a developing of Burkitts lymphoma, a non-Hodgkins lymphoma, associated with EBV infection.
Moreover the activity of PTPN6, is also implicated in a breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.

Implicated in

Entity name
T-cell lymphomas
Disease
Cutaneous T-cell lymphoma (CTCL) is generally classified as a type of non-Hodgkins lymphoma, and it represents a spectrum of diseases composed of malignant clonal helper T lymphocytes of the CD4 phenotype. Widely known variants include Sezary syndrome, Woringer-Kolopp disease (Pagetoid Reticulosis), CD8+ T-cell lymphoma, granulomatous slack skin, peripheral T-cell lymphoma, angiocentric lymphoma, adult T-cell leukemia/lymphoma, large-cell or anaplastic lymphoma, and lymphomatoid granulomatosis. Poikiloderma atrophicans vasculare, small and large plaque parapsoriasis, alopecia mucinosa, and lymphomatoid papulosis likely represent early forms of CTCL, but there is a problem to whether these represent CTCL or separate premalignant entities. Accurate diagnosis of early CTCL is difficult because of the varied clinical and histologic expressions of the disease and because of a lack of uniformity regarding diagnosis and treatment.
Prognosis
Treatment regimens in CTCL include skin-directed therapies with UVA irradiation, topical chemotherapy with mechlorethamine (nitrogen mustard) and carmustine, and electron beam radiation, as well as systemic therapies such as chemotherapy and interferons.
Note
The first hint that A-to-I RNA editing has fundamental implications in leukemic disorders derives from Beghini and co-authors, who detected altered editing events in the protein tyrosine phosphatase (PTPN6/SHP-1) transcript of patients affected by AML (Galeano et al., 2012).
The analysis of PTPN6 mRNA revealed a multiple A-I editing conversion of A7866, a branch site in IVS3 of PTPN6 mRNA causing the retention of IVS1.
Disease
Adult acute myeloid leukemia (AML) is a type of cancer in which the bone marrow makes abnormal myeloblasts (a type of white blood cell), red blood cells, or platelets. Adult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. This type of cancer usually gets worse quickly if it is not treated. It is the most common type of acute leukemia in adults. AML is also called acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia, and acute nonlymphocytic leukemia. Most AML subtypes are based on how mature (developed) the cancer cells are at the time of diagnosis and how different they are from normal cells. Acute promyelocytic leukemia (APL) is a subtype of AML that occurs when parts of two genes stick together. APL usually occurs in middle-aged adults. Symptoms of APL may include both bleeding and forming blood clots.
Prognosis
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column (intrathecal chemotherapy), an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Intrathecal chemotherapy may be used to treat adult AML that has spread, or may spread to the brain and spinal cord. Combination chemotherapy is treatment using more than one anticancer drug.
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. Stem cell transplant is a method of giving chemotherapy and replacing blood-forming cells that are abnormal or destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the bodys blood cells.
Entity name
Pyoderma gangrenosum (PG)
Disease
Pyoderma gangrenosum (PG) is a rare noninfectious neutrophilic dermatosis first described in 1930. Clinically it begins with sterile pustules that rapidly progress and turn into painful ulcers of variable depth and size with undermined violaceous borders. The legs are most commonly affected but other parts of the skin and mucous membranes may also be involved. Extracutaneous manifestations include involvement of upper airway mucosa, eye, sterile pulmonary neutrophilic infiltrates, and neutrophilic myositis. The ulcer starts as a follicular pustule with rapid growth, tissue necrosis and enlargement of the area. The surrounding skin is erythematous with infiltration end edema.
Ulcerative colitis is found in 10-15% of cases. Another associated disease is Crohns regional enteritis with a frequency close to that of ulcerative colitis. Hepatitis C, seronegative polyarticular arthritis, spondylitis, and a broad spectrum of lymphoproliferative disorders including monoclonal gammopathies, leukemia, lymphoma, and myelodysplastic syndrome have been described in association with PG. Two main variants of PG exist: classic and atypical.
Classic PG: characterized by a deep ulceration with a violaceous border that overhangs the ulcer bed. May occur anywhere on the body; but most commonly found on the legs.
Atypical PG: has a vesciculopustular component only at the border, is erosive or superficially ulcerated, and most often occurs on the dorsal surface of the hands, the extensor parts of the forearms, or the face.
Prognosis
Local care: debridement, intralesional injection of steroids or cyclosporin, topical agents to alter immune response (nitrogen mustard, steroids, acetic acid, 5-aminosalicylic acid) or inhibit infection. Systemic care: glucocorticoids (prednisone). These agents have anti-inflammatory properties and cause metabolic effects. In addition, these agents modify the bodys immune response to diverse stimuli. Immunosuppressives agents (Cyclosporine, Azathioprine, Mycophenolate, Cyclophosphamide, Tacrolimus, Chlorambucil) have immunomodulatory effects. These agents are used to improve the clinical and immunologic aspects of the disease. They may decrease autoantibody production and increase solubilization and removal of immune complexes. Immunomodulators (Thalidomide, Clofazimine).
Entity name
Sweets syndrome (SW)
Disease
Sweets syndrome (acute febrile neutrophilic dermatosis) is characterized by physical features, and pathologic findings which include fever, neutrophilia, tender erythematous skin lesions (papules, nodules, and plaques), and a diffuse infiltrate consisting predominantly of mature neutrophils that are typically located in the upper dermis. Sweets syndrome presents in three clinical settings:
Classical Sweets syndrome (CSS) usually presents in women between the age of 30 to 50 years, it is often preceded by an upper respiratory tract infection and may be associated with inflammatory bowel disease and pregnancy.
The malignancy-associated Sweets syndrome (MASS) can occur as a paraneoplastic syndrome in patients with an established cancer or individuals whose Sweets syndrome-related hematologic dyscrasia or solid tumor was previously undiscovered; MASS is most commonly related to acute myelogenous leukemia. The dermatosis can precede, follow, or appear concurrent with the diagnosis of the patients cancer.
Drug-induced Sweets syndrome (DISS) most commonly occurs in patients who have been treated with granulocyte-colony stimulating factor, however, other medications may also be associated with DISS.
Prognosis
The pathogenesis of Sweets syndrome may be multifactorial and still remains to be definitively established. Systemic corticosteroids are the therapeutic gold standard for Sweets syndrome. Horio et al. originally described the dramatic improvement in patients with Sweets syndrome who were treated with potassium iodide in 1980. He confirmed his earlier observations with a larger study in 1983. Subsequently, several other investigators have also observed similar improvement when using potassium iodide to treat patients with Sweets syndrome. Vasculitis and hypothyroidism are potential drug-induced side effects of potassium iodide. Other agents are: colchicine, indomethacin, clofazimine, cyclosporin, dapsone.

Bibliography

Pubmed IDLast YearTitleAuthors
175034112007Decreased expression level of SH2 domain-containing protein tyrosine phosphatase-1 (Shp1) is associated with progression of chronic myeloid leukaemia.Amin HM et al
76651651995Human protein tyrosine phosphatase 1C (PTPN6) gene structure: alternate promoter usage and exon skipping generate multiple transcripts.Banville D et al
110019332000RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia.Beghini A et al
176557512007Sweet's syndrome--a comprehensive review of an acute febrile neutrophilic dermatosis.Cohen PR et al
211600412011Neutrophils require SHP1 to regulate IL-1β production and prevent inflammatory skin disease.Croker BA et al
219302282012A-to-I RNA editing: the "ADAR" side of human cancer.Galeano F et al
187582442008A-to-I RNA editing and cancer: from pathology to basic science.Gallo A et al
192909262009The tyrosine kinase network regulating mast cell activation.Gilfillan AM et al
73641441980Treatment of acute febrile neutrophilic dermatosis (Sweet's Syndrome) with potassium iodide.Horio T et al
209526802010The protein tyrosine phosphatase SHP-1 modulates the suppressive activity of regulatory T cells.Iype T et al
219005012011The SHP-1 protein tyrosine phosphatase negatively modulates Akt signaling in the ghrelin/GHSR1a system.Lodeiro M et al
170817822006SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms.Nagaishi T et al
214061732011Alteration in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6/SHP1) may contribute to neutrophilic dermatoses.Nesterovitch AB et al
210816472010CEACAM1: a key regulator of vascular permeability.Nouvion AL et al
154813182004Treatment of pyoderma gangrenosum with infliximab in Crohn's disease.Sapienza MS et al
83481491993Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene.Tsui HW et al
172183192007PU.1 activates transcription of SHP-1 gene in hematopoietic cells.Wlodarski P et al
126574622003The function of the protein tyrosine phosphatase SHP-1 in cancer.Wu C et al
208588582010Lyn- and PLC-beta3-dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease.Xiao W et al
97744411998Crystal structure of the catalytic domain of protein-tyrosine phosphatase SHP-1.Yang J et al
17327481992Protein tyrosine phosphatase containing SH2 domains: characterization, preferential expression in hematopoietic cells, and localization to human chromosome 12p12-p13.Yi TL et al
109955832000Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling.Zhang J et al

Other Information

Locus ID:

NCBI: 5777
MIM: 176883
HGNC: 9658
Ensembl: ENSG00000111679

Variants:

dbSNP: 5777
ClinVar: 5777
TCGA: ENSG00000111679
COSMIC: PTPN6

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000111679ENST00000318974P29350
ENSG00000111679ENST00000399448P29350
ENSG00000111679ENST00000399448Q53XS4
ENSG00000111679ENST00000456013P29350
ENSG00000111679ENST00000535462F5GXD4
ENSG00000111679ENST00000536013F5H1V7
ENSG00000111679ENST00000538715F5H0N8
ENSG00000111679ENST00000541698F5H1Z8
ENSG00000111679ENST00000542462F5GY79
ENSG00000111679ENST00000542848F5H4Z1
ENSG00000111679ENST00000543115F5H5H9
ENSG00000111679ENST00000545153U3KQS1

Expression (GTEx)

0
50
100
150
200
250
300
350
400
450

Pathways

PathwaySourceExternal ID
Adherens junctionKEGGko04520
Jak-STAT signaling pathwayKEGGko04630
Natural killer cell mediated cytotoxicityKEGGko04650
T cell receptor signaling pathwayKEGGko04660
B cell receptor signaling pathwayKEGGko04662
Adherens junctionKEGGhsa04520
Jak-STAT signaling pathwayKEGGhsa04630
Natural killer cell mediated cytotoxicityKEGGhsa04650
T cell receptor signaling pathwayKEGGhsa04660
B cell receptor signaling pathwayKEGGhsa04662
LeishmaniasisKEGGko05140
LeishmaniasisKEGGhsa05140
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Costimulation by the CD28 familyREACTOMER-HSA-388841
PD-1 signalingREACTOMER-HSA-389948
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Antigen activates B Cell Receptor (BCR) leading to generation of second messengersREACTOMER-HSA-983695
Innate Immune SystemREACTOMER-HSA-168249
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
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Growth hormone receptor signalingREACTOMER-HSA-982772
HemostasisREACTOMER-HSA-109582
Platelet homeostasisREACTOMER-HSA-418346
Platelet sensitization by LDLREACTOMER-HSA-432142
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GPVI-mediated activation cascadeREACTOMER-HSA-114604
Cell surface interactions at the vascular wallREACTOMER-HSA-202733
PECAM1 interactionsREACTOMER-HSA-210990
Signal TransductionREACTOMER-HSA-162582
Signaling by SCF-KITREACTOMER-HSA-1433557
Regulation of KIT signalingREACTOMER-HSA-1433559
Cell-Cell communicationREACTOMER-HSA-1500931
Signal regulatory protein (SIRP) family interactionsREACTOMER-HSA-391160
CD22 mediated BCR regulationREACTOMER-HSA-5690714
Neutrophil degranulationREACTOMER-HSA-6798695

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
158701982005STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes.96
129173492003Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity.93
192047262009Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease.63
149760492004SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway.60
170792282006Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway.53
221803082012Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3.51
124382212002Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas.49
163267062006Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cells.49
119863272002Cloning and characterization of human Siglec-11. A recently evolved signaling molecule that can interact with SHP-1 and SHP-2 and is expressed by tissue macrophages, including brain microglia.47
192344872009Jak2 inhibition deactivates Lyn kinase through the SET-PP2A-SHP1 pathway, causing apoptosis in drug-resistant cells from chronic myelogenous leukemia patients.47

Citation

Alessandro Beghini ; Francesca Lazzaroni

PTPN6 (protein tyrosine phosphatase, non-receptor type 6)

Atlas Genet Cytogenet Oncol Haematol. 2012-11-01

Online version: http://atlasgeneticsoncology.org/gene/41920/ptpn6-(protein-tyrosine-phosphatase-non-receptor-type-6)