PTPN11
Encyclopedia
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D) 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.
PTPN11 is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome
as well as acute myeloid leukemia.
s in its N-terminus followed by a protein tyrosine phosphatase PTP domain. In the inactive state, the N-terminal SH2 domain binds the PTP domain and blocks access of potential substrates to the active site. Thus, Shp2 is auto-inhibited.
Upon binding to target phospho-tyrosyl residues, the N-terminal SH2 domain is released from the PTP domain, catalytically activating the enzyme by relieving this auto-inhibition.
and Leopard syndrome
.
It has also been associated with Metachondromatosis
.
(JMML). Activating Shp2 mutations have also been detected in neuroblastoma
, melanoma
, acute myeloid leukemia
, breast cancer
, lung cancer
, colorectal cancer
. These data suggests that Shp2 may be a proto-oncogene. However, it has been reported that PTPN11/Shp2 can act as either tumor promoter or suppressor
. In aged mouse model, hepatocyte-specific deletion of PTPN11/Shp2 promotes inflammatory signaling through the STAT3
pathway and hepatic inflammation/necrosis
, resulting in regenerative hyperplasia and spontaneous development of tumors. Decreased PTPN11/Shp2 expression was detected in a subfraction of human hepatocellular carcinoma (HCC)
specimens.
with
inserted by Helicobacter pylori
into gastric epithelia. Once activated by SRC phosphorylation, CagA binds to SHP2, allosterically activating it. This leads to morphological changes, abnormal mitogenic signals and sustained activity can result in apoptosis
of the host cell. Epidemiological studies have shown roles of cagA- positive H. pylori in the development of atrophic gastritis
, peptic ulcer
disease and gastric carcinoma
.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the PTPN11 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. PTPN11 is a protein tyrosine phosphatase
Protein tyrosine phosphatase
Protein tyrosine phosphatases are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. Protein tyrosine phosphorylation is a common post-translational modification that can create novel recognition motifs for protein interactions and cellular...
(PTP) Shp2.
PTPN11 is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome
Noonan syndrome
Noonan Syndrome is a relatively common autosomal dominant congenital disorder considered to be a type of dwarfism, that affects both males and females equally. It used to be referred to as the male version of Turner's syndrome ; however, the genetic causes of Noonan syndrome and Turner syndrome...
as well as acute myeloid leukemia.
Structure and function
This phosphatase, along with its paralogue, Shp1, possesses a domain structure that consists of two tandem SH2 domainSH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
s in its N-terminus followed by a protein tyrosine phosphatase PTP domain. In the inactive state, the N-terminal SH2 domain binds the PTP domain and blocks access of potential substrates to the active site. Thus, Shp2 is auto-inhibited.
Upon binding to target phospho-tyrosyl residues, the N-terminal SH2 domain is released from the PTP domain, catalytically activating the enzyme by relieving this auto-inhibition.
Genetic diseases associated with PTPN11
Missense mutations in the PTPN11 locus are associated with both Noonan syndromeNoonan syndrome
Noonan Syndrome is a relatively common autosomal dominant congenital disorder considered to be a type of dwarfism, that affects both males and females equally. It used to be referred to as the male version of Turner's syndrome ; however, the genetic causes of Noonan syndrome and Turner syndrome...
and Leopard syndrome
Leopard syndrome
LEOPARD syndrome - is part of a group called Ras/MAPK pathway syndromes - is a rare autosomal dominant, multisystem disease caused by a...
.
It has also been associated with Metachondromatosis
Metachondromatosis
Metachondromatosis is an autosomal dominant skeletal disorder affecting the growth of bones, leading to multiple enchondromas and osteochondromas. Affects mainly tubular bones, though can involve the vertebrae.-Genetics:...
.
Noonan syndrome
In the case of Noonan syndrome, mutations are broadly distributed throughout the coding region of the gene but all appear to result in hyper-activated, or unregulated mutant forms of the protein. Most of these mutations disrupt the binding interface between the N-SH2 domain and catalytic core necessary for the enzyme to maintain its auto-inhibited conformation.Leopard syndrome
The mutations that cause Leopard syndrome are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants. It is currently unclear how mutations that give rise to mutant variants of Shp2 with biochemically opposite characteristics result in similar human genetic syndromes.Cancer associated with PTPN11
Patients with a subset of Noonan syndrome PTPN11 mutations also have a higher prevalence of juvenile myelomonocytic leukemiasJuvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia is a serious chronic leukemia that affects children mostly aged 4 and younger. The average age of patients at diagnosis is 2 years old. The World Health Organization has included JMML in the category of Myelodysplastic and Myeloproliferative disorders...
(JMML). Activating Shp2 mutations have also been detected in neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
, melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
, acute myeloid leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
, breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
, colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
. These data suggests that Shp2 may be a proto-oncogene. However, it has been reported that PTPN11/Shp2 can act as either tumor promoter or suppressor
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
. In aged mouse model, hepatocyte-specific deletion of PTPN11/Shp2 promotes inflammatory signaling through the STAT3
STAT3
Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
pathway and hepatic inflammation/necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
, resulting in regenerative hyperplasia and spontaneous development of tumors. Decreased PTPN11/Shp2 expression was detected in a subfraction of human hepatocellular carcinoma (HCC)
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
specimens.
Interactions
PTPN11 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with
- Cbl geneCbl geneCbl is a mammalian gene encoding several proteins including E3 ubiquitin-protein ligase CBL involved in cell signalling and protein ubiquitination...
, - CD117CD117Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...
, - CD31CD31Platelet endothelial cell adhesion molecule also known as cluster of differentiation 31 is a protein that in human is encoded by the PECAM1 gene found on chromosome 17...
, - CEACAM1CEACAM1Carcinoembryonic antigen-related cell adhesion molecule 1 also known as CD66a , is a human gene.-Interactions:...
, - Epidermal growth factor receptorEpidermal growth factor receptorThe epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
, - ErkExtracellular signal-regulated kinasesIn molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
- FRS2FRS2Fibroblast growth factor receptor substrate 2 is a protein that in humans is encoded by the FRS2 gene.-Interactions:FRS2 has been shown to interact with PRKCI, Grb2, PTPN11, Fibroblast growth factor receptor 1, TrkA, Cbl gene and SOS1....
, - GAB1GAB1GRB2-associated-binding protein 1 is a protein that in humans is encoded by the GAB1 gene.-Interactions:GAB1 has been shown to interact with Grb2, PIK3R1, PTPN11, CRKL, PLCG1 and MAP3K3.-Further reading:...
, - GAB2GAB2GRB2-associated-binding protein 2 is a protein that in humans is encoded by the GAB2 gene.The protein encoded by this gene, GAB2 is an adaptor protein serving as principal activator of Phosphatidylinositol 3-kinase...
, - Glycoprotein 130Glycoprotein 130Glycoprotein 130 is a transmembrane protein which is the founding member of the class of all cytokine receptors. It forms one subunit of type I cytokine receptors within the IL-6 receptor family...
, - Grb2Grb2Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, - Growth hormone receptorGrowth hormone receptorGrowth hormone receptor is a protein that in humans is encoded by the GHR gene. GHR orthologs have been identified in most mammals.-Interactions:...
, - HoxA10,
- Insulin receptorInsulin receptorIn molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
, - Insulin-like growth factor 1 receptor,
- IRS1IRS1Insulin receptor substrate 1 is a protein that in humans is encoded by the IRS-1 gene.-Function:Insulin receptor substrate 1 plays a key role in transmitting signals from the insulin and insulin-like growth factor-1 receptors to intracellular pathways PI3K / Akt and Erk MAP kinase...
, - Janus kinase 1Janus kinase 1JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain of type I cytokine receptors, to elicit signals from the IL-2 receptor family , the IL-4 receptor family , the gp130 receptor family JAK1 is a human...
, - Janus kinase 2Janus kinase 2Janus kinase 2 is a human protein that has been implicated in signaling by members of the type II cytokine receptor family , the GM-CSF receptor family , the gp130 receptor family , and the single chain receptors...
, - LAIR1LAIR1Leukocyte-associated immunoglobulin-like receptor 1 is a protein that in humans is encoded by the LAIR1 gene. LAIR1 has also been designated as CD305 .-Interactions:...
, - LRP1LRP1Low density lipoprotein receptor-related protein 1 , also known as alpha-2-macroglobulin receptor , apolipoprotein E receptor or cluster of differentiation 91 , is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis...
, - PDGFRBPDGFRBBeta-type platelet-derived growth factor receptor is a protein that in humans is encoded by the PDGFRB gene.-Interactions:PDGFRB has been shown to interact with PTPN11, NCK1, Grb2, Caveolin 1, PDGFRA, Sodium-hydrogen antiporter 3 regulator 1, RAS p21 protein activator 1, CRK, SHC1 and...
, - PI3K → AktAKTAkt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
- PLCG2PLCG21-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 is an enzyme that in humans is encoded by the PLCG2 gene.- Function :Enzymes of the phospholipase C family catalyze the hydrolysis of phospholipids to yield diacylglycerols and water-soluble phosphorylated derivatives of the lipid...
, - PTK2BPTK2BProtein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the PTK2B gene.-Protein:-Interactions:PTK2B has been shown to interact with PTPN11, PTPN6, PITPNM1, Gelsolin, Src, GRIN2A, Ewing sarcoma breakpoint region 1, RB1CC1, TGFB1I1, NPHP1, BCAR1, FYN, DLG4, DLG3, DDEF2, Cbl gene, RAS...
, - Ras
- SLAMF1SLAMF1Signaling lymphocytic activation molecule is a protein that in humans is encoded by the SLAMF1 gene.SLAMF1 has also recently has been designated CD150 .-Interactions:...
, - SOCS3SOCS3Suppressor of cytokine signaling 3 is a protein that in humans is encoded by the SOCS3 gene.-Interactions:SOCS3 has been shown to interact with PTPN11, Glycoprotein 130, Erythropoietin receptor, Janus kinase 2, RAS p21 protein activator 1 and Insulin-like growth factor 1 receptor.-Regulation:There...
, - SOS1SOS1Son of sevenless homolog 1 is a protein that in humans is encoded by the SOS1 gene.Recent studies also show that mutations in Sos1 can cause Noonan syndrome and hereditary gingival fibromatosis type 1. Noonan syndrome has also been shown to be caused by mutations in KRAS and PTPN11 genes...
, - STAT3STAT3Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
, - STAT5ASTAT5ASignal transducer and activator of transcription 5A is a protein that in humans is encoded by the STAT5A gene. STAT5A orthologs have been identified in several placentals for which complete genome data are available.-Interactions:...
, and - STAT5BSTAT5BSignal transducer and activator of transcription 5B is a protein that in humans is encoded by the STAT5B gene. STAT5B orthologs have been identified in most placentals for which complete genome data are available.-Interactions:...
.
H Pylori CagA virulence factor
CagA is a protein and virulence factorVirulence factor
Virulence factors are molecules expressed and secreted by pathogens that enable them to achieve the following:* colonization of a niche in the host...
inserted by Helicobacter pylori
Helicobacter pylori
Helicobacter pylori , previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were...
into gastric epithelia. Once activated by SRC phosphorylation, CagA binds to SHP2, allosterically activating it. This leads to morphological changes, abnormal mitogenic signals and sustained activity can result in apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
of the host cell. Epidemiological studies have shown roles of cagA- positive H. pylori in the development of atrophic gastritis
Atrophic gastritis
Atrophic gastritis is a process of chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues...
, peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
disease and gastric carcinoma
Stomach cancer
Gastric cancer, commonly referred to as stomach cancer, can develop in any part of the stomach and may spread throughout the stomach and to other organs; particularly the esophagus, lungs, lymph nodes, and the liver...
.