PTPN11

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Protein tyrosine phosphatase, non-receptor type 11
Shp-2.JPG
PDB rendering based on 2shp.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PTPN11 ; BPTP3; CFC; NS1; PTP-1D; PTP2C; SH-PTP2; SH-PTP3; SHP2
External IDs OMIM176876 MGI99511 HomoloGene2122 ChEMBL: 3864 GeneCards: PTPN11 Gene
EC number 3.1.3.48
RNA expression pattern
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:
112.86 – 112.95 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.[1][2]

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.[3]

Structure and function[edit]

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[edit]

Missense mutations in the PTPN11 locus are associated with both Noonan syndrome and Leopard syndrome.

It has also been associated with Metachondromatosis.[4]

Noonan syndrome[edit]

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.[5]

Leopard syndrome[edit]

The mutations that cause Leopard syndrome are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants.[6] 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[edit]

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.[7] 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.[8] 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.[8] 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.[9]

Interactions[edit]

PTPN11 has been shown to interact with

H Pylori CagA virulence factor[edit]

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.[64]

References[edit]

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  2. ^ Freeman RM, Plutzky J, Neel BG (December 1992). "Identification of a human Src homology 2-containing protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew". Proc. Natl. Acad. Sci. U.S.A. 89 (23): 11239–43. doi:10.1073/pnas.89.23.11239. PMC 50525. PMID 1280823. 
  3. ^ "Entrez Gene: PTPN11 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1)". 
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  6. ^ Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG (March 2006). "PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects". J. Biol. Chem. 281 (10): 6785–92. doi:10.1074/jbc.M513068200. PMID 16377799. 
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Further reading[edit]

  • Marron MB, Hughes DP, McCarthy MJ, et al. (2000). "Tie-1 receptor tyrosine kinase endodomain interaction with SHP2: potential signalling mechanisms and roles in angiogenesis.". Adv. Exp. Med. Biol. 476: 35–46. doi:10.1007/978-1-4615-4221-6_3. PMID 10949653. 
  • Carter-Su C, Rui L, Stofega MR (2000). "SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone.". Recent Prog. Horm. Res. 55: 293–311. PMID 11036942. 
  • Ion A, Tartaglia M, Song X, et al. (2002). "Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome.". Hum. Genet. 111 (4-5): 421–7. doi:10.1007/s00439-002-0803-6. PMID 12384786. 
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