PTPN11

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.^[5][6]

PTPN11
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2SHP, 3B7O, 3MOW, 3O5X, 3TKZ, 3TL0, 4DGP, 4DGX, 4GWF, 4H1O, 4JE4, 4JEG, 3ZM0, 3ZM1, 3ZM2, 3ZM3, 4H34, 4JMG, 4NWF, 4NWG, 4OHD, 4OHE, 4OHH, 4OHI, 4OHL, 4PVG, 4RDD, 4QSY, 5DF6, 5IBS, 5EHP, 5EHR, 5I6V, 5IBM
Identifiers
Aliases	PTPN11, BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2, protein tyrosine phosphatase, non-receptor type 11, protein tyrosine phosphatase non-receptor type 11
External IDs	OMIM: 176876; MGI: 99511; HomoloGene: 2122; GeneCards: PTPN11; OMA:PTPN11 - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q24.13 Start 112,418,351 bp[1] End 112,509,918 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 F Start 121,268,596 bp[2] End 121,329,460 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in internal globus pallidus dorsal motor nucleus of vagus nerve Brodmann area 23 visceral pleura parietal pleura subthalamic nucleus pars reticulata inferior olivary nucleus Epithelium of choroid plexus external globus pallidus Top expressed in renal corpuscle Epithelium of choroid plexus utricle medullary collecting duct retinal pigment epithelium substantia nigra ciliary body iris endocardial cushion primitive streak More reference expression data BioGPS More reference expression data
Gene ontology Molecular function phospholipase binding phosphoprotein phosphatase activity insulin receptor binding phosphatase activity receptor tyrosine kinase binding peptide hormone receptor binding protein binding non-membrane spanning protein tyrosine phosphatase activity hydrolase activity phosphatidylinositol-4,5-bisphosphate 3-kinase activity 1-phosphatidylinositol-3-kinase activity cell adhesion molecule binding protein tyrosine phosphatase activity phosphotyrosine residue binding protein domain specific binding D1 dopamine receptor binding insulin receptor substrate binding protein tyrosine kinase binding protein kinase binding Cellular component cytoplasm cytosol mitochondrion nucleus nucleoplasm protein-containing complex Biological process dephosphorylation megakaryocyte development positive regulation of signal transduction negative regulation of insulin secretion regulation of cell adhesion mediated by integrin atrioventricular canal development intestinal epithelial cell migration organ growth epidermal growth factor receptor signaling pathway negative regulation of growth hormone secretion axonogenesis glucose homeostasis regulation of protein export from nucleus multicellular organism growth regulation of multicellular organism growth lipid metabolism ephrin receptor signaling pathway abortive mitotic cell cycle DNA damage checkpoint signaling protein dephosphorylation T cell costimulation platelet formation microvillus organization positive regulation of mitotic cell cycle genitalia development platelet activation fibroblast growth factor receptor signaling pathway heart development brain development regulation of type I interferon-mediated signaling pathway hormone-mediated signaling pathway integrin-mediated signaling pathway Bergmann glial cell differentiation homeostasis of number of cells within a tissue inner ear development platelet-derived growth factor receptor signaling pathway negative regulation of cortisol secretion peptidyl-tyrosine dephosphorylation ERBB signaling pathway negative regulation of hormone secretion triglyceride metabolic process hormone metabolic process positive regulation of hormone secretion negative regulation of cell adhesion mediated by integrin regulation of protein-containing complex assembly face morphogenesis cerebellar cortex formation leukocyte migration multicellular organismal reproductive process phosphatidylinositol phosphate biosynthetic process neurotrophin TRK receptor signaling pathway phosphatidylinositol-3-phosphate biosynthetic process axon guidance positive regulation of ERK1 and ERK2 cascade cellular response to epidermal growth factor stimulus positive regulation of protein kinase B signaling cytokine-mediated signaling pathway interleukin-6-mediated signaling pathway cellular response to cytokine stimulus cellular response to mechanical stimulus positive regulation of interferon-beta production positive regulation of interleukin-6 production positive regulation of tumor necrosis factor production positive regulation of glucose import positive regulation of insulin receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5781 19247 Ensembl ENSG00000179295 ENSMUSG00000043733 UniProt Q06124 P35235 RefSeq (mRNA) NM_002834 NM_080601 NM_001330437 NM_001374625 NM_018508 NM_001109992 NM_011202 RefSeq (protein) NP_001317366 NP_002825 NP_542168 NP_001361554 NP_001103462 NP_035332 Location (UCSC) Chr 12: 112.42 – 112.51 Mb Chr 5: 121.27 – 121.33 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[7]

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. At least 79 disease-causing mutations in this gene have been discovered.^[8]

It has also been associated with metachondromatosis.^[9]

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.^[10]

Leopard syndrome

The mutations that cause Leopard syndrome are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants.^[11] 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.^[12] Recently, a relatively high prevalence of PTPN11 mutations (24%) were detected by next-generation sequencing in a cohort of NPM1-mutated acute myeloid leukemia patients,^[13] although the prognostic significance of such associations has not been clarified. 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.^[14] 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.^[14] 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.^[15]

Interactions

PTPN11 has been shown to interact with

• CagA,^[15]
• Cbl gene,^[16]
• CD117,^[17][18]
• CD31,^{[19][20][21][22]}
• CEACAM1,^[23]
• Epidermal growth factor receptor,^[24][25]
• Erk^[26][27]
• FRS2,^[28][29][30]
• GAB1,^[31][32]
• GAB2,^{[33][34][35][36]}
• GAB3,^[37]
• Glycoprotein 130,^[38][39][40]
• Grb2,^{[30][41][42][43][44][45][46][47][48]}
• Growth hormone receptor,^[49][50]
• HoxA10,^[51]
• Insulin receptor,^[52][53]
• Insulin-like growth factor 1 receptor,^[54][55]
• IRS1,^[56][57]
• Janus kinase 1,^[38][41]
• Janus kinase 2,^[41][58][59]
• LAIR1,^[60][61]
• LRP1,^[62]
• PDGFRB,^[63][64]
• PI3K → Akt^[26]
• PLCG2,^[33]
• PTK2B,^[65]
• Ras^[26][27]
• SLAMF1,^[66][67]
• SOCS3,^[38]
• SOS1,^[30][68]
• STAT3,^[14]
• STAT5A,^[69][70] and
• STAT5B.^[69]

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.^[71]

References

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Further reading

• Marron MB, Hughes DP, McCarthy MJ, Beaumont ER, Brindle NP (2000). "Tie-1 Receptor Tyrosine Kinase Endodomain Interaction with SHP2: Potential Signalling Mechanisms and Roles in Angiogenesis". Angiogenesis. Advances in Experimental Medicine and Biology. Vol. 476. pp. 35–46. doi:10.1007/978-1-4615-4221-6_3. ISBN 978-1-4613-6895-3. 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, Kalidas K, van der Burgt I, Shaw AC, Ming JE, Zampino G, Zackai EH, Dean JC, Somer M, Parenti G, Crosby AH, Patton MA, Gelb BD, Jeffery S (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. S2CID 27085702.
• Hugues L, Cavé H, Philippe N, Pereira S, Fenaux P, Preudhomme C (2006). "Mutations of PTPN11 are rare in adult myeloid malignancies". Haematologica. 90 (6): 853–4. PMID 15951301.
• Tartaglia M, Gelb BD (2005). "Germ-line and somatic PTPN11 mutations in human disease". European Journal of Medical Genetics. 48 (2): 81–96. doi:10.1016/j.ejmg.2005.03.001. PMID 16053901.
• Ogata T, Yoshida R (2006). "PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes". Pediatric Endocrinology Reviews. 2 (4): 669–74. PMID 16208280.
• Feng GS (2007). "Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation". Cell Res. 17 (1): 37–41. doi:10.1038/sj.cr.7310140. PMID 17211446.
• Edouard T, Montagner A, Dance M, Conte F, Yart A, Parfait B, Tauber M, Salles JP, Raynal P (2007). "How do Shp2 mutations that oppositely influence its biochemical activity result in syndromes with overlapping symptoms?". Cell. Mol. Life Sci. 64 (13): 1585–90. doi:10.1007/s00018-007-6509-0. PMC 11136329. PMID 17453145. S2CID 25934330.

External links

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