PTPN11

Protein tyrosine phosphatase, non-receptor type 11
250px PDB rendering based on 2shp.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2SHP, 3B7O, 3MOW, 3O5X, 3TKZ, 3TL0, 3ZM0, 3ZM1, 3ZM2, 3ZM3, 4DGP, 4DGX, 4GWF, 4H1O, 4H34, 4JE4, 4JEG, 4JMG, 4NWF, 4NWG, 4OHD, 4OHE, 4OHH, 4OHI, 4OHL, 4PVG
Identifiers
Symbols	PTPN11 ; BPTP3; CFC; NS1; PTP-1D; PTP2C; SH-PTP2; SH-PTP3; SHP2
External IDs	OMIM: 176876 MGI: 99511 HomoloGene: 2122 ChEMBL: 3864 GeneCards: PTPN11 Gene
EC number	3.1.3.48
Gene ontology Molecular function • phosphoprotein phosphatase activity • protein tyrosine phosphatase activity • non-membrane spanning protein tyrosine phosphatase activity • SH3/SH2 adaptor activity • insulin receptor binding • protein binding • protein domain specific binding • receptor tyrosine kinase binding • D1 dopamine receptor binding • phospholipase binding • insulin receptor substrate binding • peptide hormone receptor binding Cellular component • nucleus • cytoplasm • mitochondrion • cytosol • protein complex Biological process • DNA damage checkpoint • activation of MAPK activity • triglyceride metabolic process • epidermal growth factor receptor signaling pathway • integrin-mediated signaling pathway • axon guidance • brain development • heart development • blood coagulation • insulin receptor signaling pathway • fibroblast growth factor receptor signaling pathway • hormone-mediated signaling pathway • cytokine-mediated signaling pathway • platelet formation • T cell costimulation • microvillus organization • abortive mitotic cell cycle • regulation of cell adhesion mediated by integrin • negative regulation of cell adhesion mediated by integrin • multicellular organism growth • organ growth • peptidyl-tyrosine dephosphorylation • megakaryocyte development • atrioventricular canal development • Fc-epsilon receptor signaling pathway • ERBB signaling pathway • regulation of multicellular organism growth • hormone metabolic process • glucose homeostasis • innate immune response • positive regulation of mitotic cell cycle • negative regulation of insulin secretion • regulation of protein export from nucleus • positive regulation of hormone secretion • platelet-derived growth factor receptor signaling pathway • neurotrophin TRK receptor signaling pathway • ephrin receptor signaling pathway • phosphatidylinositol-mediated signaling • multicellular organismal reproductive process • genitalia development • inner ear development • homeostasis of number of cells within a tissue • leukocyte migration • negative regulation of cortisol secretion • negative regulation of growth hormone secretion • face morphogenesis • interferon-gamma-mediated signaling pathway • regulation of interferon-gamma-mediated signaling pathway • type I interferon signaling pathway • regulation of type I interferon-mediated signaling pathway • intestinal epithelial cell migration • positive regulation of ERK1 and ERK2 cascade • positive regulation of glucose import in response to insulin stimulus Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE PTPN11 gnf1h09380 s at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5781	19247
Ensembl	ENSG00000179295	ENSMUSG00000043733
UniProt	Q06124	P35235
RefSeq (mRNA)	NM_002834	NM_001109992
RefSeq (protein)	NP_002825	NP_001103462
Location (UCSC)	Chr 12: 112.42 – 112.51 Mb	Chr 5: 121.13 – 121.19 Mb
PubMed search	[1]	[2]

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.

Structure and function

This phosphatase, along with its paralogue, Shp1, possesses a domain structure that consists of two tandem SH2 domains 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 syndrome and Leopard syndrome.

It has also been associated with Metachondromatosis.

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 leukemias (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. The bacterium Helicobacter pylori has been associated with gastric cancer, and this is thought to be mediated in part by the interaction of its virulence factor CagA with SHP2.

Interactions

PTPN11 has been shown to interact with

• CagA,
• Cbl gene,
• CD117,
• CD31,
• CEACAM1,
• Epidermal growth factor receptor,
• Erk
• FRS2,
• GAB1,
• GAB2,
• Glycoprotein 130,
• Grb2,
• Growth hormone receptor,
• HoxA10,
• Insulin receptor,
• Insulin-like growth factor 1 receptor,
• IRS1,
• Janus kinase 1,
• Janus kinase 2,
• LAIR1,
• LRP1,
• PDGFRB,
• PI3K → Akt
• PLCG2,
• PTK2B,
• Ras
• SLAMF1,
• SOCS3,
• SOS1,
• STAT3,
• STAT5A, and
• STAT5B.

H Pylori CagA virulence factor

CagA is a protein and virulence factor 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.

External links

• GeneReviews/NCBI/NIH/UW entry on Noonan syndrome