PTPN1

Last updated
PTPN1
Protein PTPN1 PDB 1a5y.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PTPN1 , PTP1B, protein tyrosine phosphatase, non-receptor type 1, protein tyrosine phosphatase non-receptor type 1
External IDs OMIM: 176885 MGI: 97805 HomoloGene: 2119 GeneCards: PTPN1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002827
NM_001278618

NM_011201

RefSeq (protein)

NP_001265547
NP_002818

NP_035331

Location (UCSC) Chr 20: 50.51 – 50.59 Mb Chr 2: 167.77 – 167.82 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B (PTP1B) is an enzyme that is the founding member of the protein tyrosine phosphatase (PTP) family. In humans it is encoded by the PTPN1 gene. [5] PTP1B is a negative regulator of the insulin signaling pathway and is considered a promising potential therapeutic target, in particular for treatment of type 2 diabetes. [6] It has also been implicated in the development of breast cancer and has been explored as a potential therapeutic target in that avenue as well. [7] [8] [9]

Structure and function

PTP1B was first isolated from a human placental protein extract, [10] [11] but it is expressed in many tissues. [12] PTP1B is localized to the cytoplasmic face of the endoplasmic reticulum. [13] PTP1B can dephosphorylate the phosphotyrosine residues of the activated insulin receptor kinase. [11] [14] [15] In mice, genetic ablation of PTPN1 results in enhanced insulin sensitivity. [16] [17] Several other tyrosine kinases, including epidermal growth factor receptor, [18] insulin-like growth factor 1 receptor, [19] colony stimulating factor 1 receptor, [20] c-Src, [21] Janus kinase 2, [22] TYK2, [22] and focal adhesion kinase [23] as well as other tyrosine-phosphorylated proteins, including BCAR1, [24] DOK1, [25] beta-catenin [26] and cortactin [27] have also been described as PTP1B substrates.

The first crystal structure of the PTP1B catalytic domain revealed that the catalytic site exists within a deep cleft of the protein formed by three loops including the WPD loop with the Asp181 residue, a pTyr loop with the Tyr46 residue and a Q loop with the Gln262 residue. [28] [29] The pTyr loop and Tyr46 residue are located on the surface of the protein, and thus help to determine the depth a substrate can obtain within the cleft. This acts as a means of driving selectivity, as substrates containing smaller phosphoresidues cannot reach the site of catalytic activity at the base of the cleft. [28] Upon substrate binding, PTP1B undergoes a structural modification in which the WPD loop closes around the substrate, introducing stabilizing pi stacking interactions between the aromatic rings of the phosphotyrosine (pTyr) substrate residue and the Phe182 residue on the WPD loop. [29]

Mechanism

The phosphatase activity of PTP1B occurs via a two-step mechanism. [28] The dephosphorylation of the pTyr substrate occurs in the first step, while the enzyme intermediates are broken down during the second step. During the first step, there is a nucleophilic attack at the phosphocenter by the reduced Cys215 residue, followed by subsequent protonation by Asp181 to yield the neutral tyrosine phenol. The active enzyme is regenerated after the thiophosphate intermediate is hydrolyzed, which is facilitated by the hydrogen bonding interactions of Gln262 and Asp181 that help to position in the water molecule at the desired site of nucleophillic attack.

Two step mechanism of PTP1B phosphatase activity. PTP1B Mechanism.png
Two step mechanism of PTP1B phosphatase activity.

Regulation

The Cys215 residue is essential for the enzymatic activity of PTP1B and similar cysteine residues are required for the activity of other members of the Class I PTP family. [30] The thiolate anion form is needed for nucleophilic activity but it is susceptible to oxidation by reactive oxygen species (ROS) in the cell which would render the enzyme non-functional. This cysteine residue has been shown to oxidize under increased cellular concentrations of hydrogen peroxide (H2O2), produced in response to EGF and insulin signaling. [31] [32] [33] The thiolate is oxidized to a sulfenic acid, which is converted to a sulfenyl amide after reacting with the adjacent Ser216 residue. [34] This modification of the Cys215 residue prevents further oxidation of the residue which would be irreversible, and also induces a structural change in the cleft of the active site such that substrates may not bind. [34] [35] This oxidation can be reversed through reduction by glutathione and acts as a means of regulating PTP1B activity. [35] Phosphorylation of the Ser50 residue has also been shown as a point of allosteric regulation of PTP1B, in which the phosphorylated state of the enzyme is inactive. [36]

Interactions

PTPN1 has been shown to interact with BCAR1, [24] epidermal growth factor receptor, [37] [38] Grb2 [24] [39] and IRS1. [36] [39] Vascular endothelial growth factor Receptor-2 [40] and Vascular endothelial growth factor via PGC1-alpha/ERR-alpha [41]

Clinical significance

PTP1B has clinical implications in the treatment of type 2 diabetes as well as cancer. Gene knockout studies conducted in murine models has provided substantial evidence for the role PTP1B plays in the regulation of insulin signalling and the development of obesity. [16] [17] PTPN1 knockout mice kept on high fat diets showed a resistance to obesity and an increased degree of insulin sensitivity as compared to their wild-type counterparts. [16] [17] As such, the design and development of PTP1B inhibitors is a growing field of research for the treatment of type 2 diabetes and obesity. [42]

Although PTP1B is generally studied as a regulator of metabolism, some research suggest it may have a role in tumor development, though whether it is oncogenic or tumor suppressive is unclear, as there is data in support of both arguments. The high ROS concentrations within cancer cells provide an environment for potential constitutive inactivation of PTP1B and it has been shown in two human cancer cell lines HepG2 and A431, that up to 40% of the Cys215 residues in PTP1B can be selectively irreversibly oxidized under these cellular conditions resulting in non-functional PTP1B. [43] In addition, PTPN1 genetic ablation in p53 deficient mice resulted in an increased incidence of lymphomas and a decrease in overall survival rates. [44] In contrast, the PTPN1 gene has been shown to be overexpressed in conjunction with HER2 in breast cancer cases. [8] Murine models of HER2 overexpression in conjunction with PTPN1 knockout resulted in delayed tumor growth and with fewer observed metastases to the lung suggesting that PTPN1 may have an oncogenic role in breast cancer. [8] [9]

See also

Related Research Articles

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

<span class="mw-page-title-main">PTPN11</span> Protein-coding gene in humans

Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2.

<span class="mw-page-title-main">Adapter molecule crk</span> Protein-coding gene in the species Homo sapiens

Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the CRK gene.

<span class="mw-page-title-main">PTPN6</span> Protein-coding gene in humans

Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the PTPN6 gene.

<span class="mw-page-title-main">IRS2</span> Protein-coding gene in the species Homo sapiens

Insulin receptor substrate 2 is a protein that in humans is encoded by the IRS2 gene.

<span class="mw-page-title-main">PTPN12</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein phosphatase non-receptor type 12 is an enzyme that in humans is encoded by the PTPN12 gene.

<span class="mw-page-title-main">PTPRA</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase alpha is an enzyme that in humans is encoded by the PTPRA gene.

<span class="mw-page-title-main">PTPRF</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase F is an enzyme that, in humans, is encoded by the PTPRF gene.

<span class="mw-page-title-main">Signal-regulatory protein alpha</span> Protein-coding gene in the species Homo sapiens

Signal regulatory protein α (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells or neurons.

<span class="mw-page-title-main">PTPN2</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein phosphatase non-receptor type 2 is an enzyme that in humans is encoded by the PTPN2 gene.

<span class="mw-page-title-main">PTPRJ</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase eta is an enzyme that in humans is encoded by the PTPRJ gene.

<span class="mw-page-title-main">PTPN7</span> Protein-coding gene in the species Homo sapiens

Protein tyrosine phosphatase non-receptor type 7 is an enzyme that in humans is encoded by the PTPN7 gene.

<span class="mw-page-title-main">PTPRM</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the PTPRM gene.

<span class="mw-page-title-main">PTP4A1</span> Protein-coding gene in the species Homo sapiens

Protein tyrosine phosphatase type IVA 1 is an enzyme that in humans is encoded by the PTP4A1 gene.

<span class="mw-page-title-main">PTPRS</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase S, also known as R-PTP-S, R-PTP-sigma, or PTPσ, is an enzyme that in humans is encoded by the PTPRS gene.

<span class="mw-page-title-main">PTPRU</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase PCP-2, is an enzyme that in humans is encoded by the PTPRU gene.

<span class="mw-page-title-main">PSTPIP1</span> Enzyme found in humans

Proline-serine-threonine phosphatase-interacting protein 1 is an enzyme that in humans is encoded by the PSTPIP1 gene.

<span class="mw-page-title-main">PTPN3</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein phosphatase non-receptor type 3 is an enzyme that in humans is encoded by the PTPN3 gene.

<span class="mw-page-title-main">PTPN9</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein phosphatase non-receptor type 9 is an enzyme that in humans is encoded by the PTPN9 gene.

<span class="mw-page-title-main">PTPRH</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase H is an enzyme that in humans is encoded by the PTPRH gene.

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