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

t(11;14)(q13;q32)
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Gene Section
Review
PTPN1 (protein tyrosine phosphatase, nonreceptor type 1)
Giuseppe Leuzzi, Alberto Calderone, Luisa Castagnoli
Department of Biology, University of Rome Tor Vergata, Rome, Italy (GL, AC, LC)
Published in Atlas Database: January 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/PTPN1ID41909ch20q13.html
DOI: 10.4267/2042/47339
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Transcription
Other names: PTP1B
HGNC (Hugo): PTPN1
Location: 20q13.13
Local order: According to NCBI Map Viewer, PTPN1
gene is located between: LOC284751, COX6CP2
(cytochrome c oxidase subunit VIc pseudogene 2) (in
centromeric position), MIR645 (microRNA 645) and
FAM65c (family with sequence similarity 65, member
c) (in telomeric position).
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)).
DNA/RNA
Pseudogene
Note
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).
No human pseudogene for PTPN1 has been identified.
Description
Localisation
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).
Endoplasmic
reticulum
membrane;
membrane protein; cytoplasmic side.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
Protein
Description
Size: 435 amino acids; 49967 Da.
Expression
PTP1B is expressed abundantly.
peripheral
Function
Belongs to the protein-tyrosine phosphatase family.
Non-receptor class 1 subfamily; IUBMB enzyme
nomenclature: EC 3.1.3.48.
PTP1B (P18031 in UniProtKB) has an N-terminal
412
PTPN1 (protein tyrosine phosphatase, non-receptor type 1)
Leuzzi G, et al.
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).
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.
Oncogenesis
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 phosphotyrosines 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).
Mutations
Note
The
1484insG
variation
(OMIM
variation
(176885.0001)) (Meshkani et al., 2007), the singlenucleotide polymorphism (SNP) 981CT (Mok et al.,
2002), VS6+G82A polymorphism, G82G, Pro387Leu
variant (Ukkola et al., 2005).
Implicated in
Various diseases and cancers
Note
PTP1B is involved in direct/enzymatic or indirect
interactions with several proteins. In the figure, the
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.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
413
PTPN1 (protein tyrosine phosphatase, non-receptor type 1)
Leuzzi G, et al.
In 2006, Akasaki et al. proposed a molecular
mechanism to explain the involvement of PTP1B in the
proapoptotic effect caused by troglitazone, an antidiabetic 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 phosphotyrosine 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)
Breast cancer
Note
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 ErbB2induced 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 MCF7 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).
Autoimmunity and B-cell lymphomas
Note
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 nonHodgkin 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 IL4/Jak/STAT6 pathway (Lu et al., 2008).
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
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PTPN1 (protein tyrosine phosphatase, non-receptor type 1)
Leuzzi G, et al.
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).
Susceptibility to insulin resistance and
metabolic syndrome
Note
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 pTyr1163. 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 trisphosphorylated 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
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(6)
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This article should be referenced as such:
Leuzzi G, Calderone A, Castagnoli L. PTPN1 (protein tyrosine
phosphatase, non-receptor type 1). Atlas Genet Cytogenet
Oncol Haematol. 2012; 16(6):412-416.
Burdon KP, Bento JL, Langefeld CD, Campbell JK, Carr JJ,
Wagenknecht LM, Herrington DM, Freedman BI, Rich SS,
Bowden DW. Association of protein tyrosine phosphatase-N1
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416