PTPN11

Protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1)
File:PBB Protein PTPN11 image.jpg PDB rendering based on 1aya.
Available structures PDB Ortholog search: Template:Homologene2PDBe PDBe, Template:Homologene2uniprot RCSB List of PDB id codes 1aya​, 1ayb​, 1ayc​, 1ayd​, 2shp​
Identifiers
Symbols	PTPN11 ; BPTP3; CFC; MGC14433; NS1; PTP-1D; PTP2C; SH-PTP2; SH-PTP3; SHP2
External IDs	Template:OMIM5 Template:MGI HomoloGene: 2122
Gene ontology Molecular function Template:GNF GO Template:GNF GO Template:GNF GO Biological process Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO Template:GNF GO
RNA expression pattern
File:PBB GE PTPN11 gnf1h09380 s at tn.png
More reference expression data
Orthologs
Template:GNF Ortholog box
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	n/a	n/a
PubMed search	n/a	n/a

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

PTPN11 is a gene encoding the protein tyrosine phosphatase (PTP), Shp2. The protein encoded by this gene 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 releaving this auto-inhibition.

Genetic diseases associated with PTPN11

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

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.

PTPN11 mutations in cancer

Patients with a subset of Noonan syndrome PTPN11 mutations also have a higher prevalence of juvenile myelomonocytic leukemias. Activating Shp2 mutations have also been detected in neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, Colon Cancer. These data suggests that Shp2 may be a proto-oncogene.

Further reading

• 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. PMID 10949653.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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.CS1 maint: Multiple names: authors list (link)
• 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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• Hugues L, Cavé H, Philippe N; et al. (2006). "Mutations of PTPN11 are rare in adult myeloid malignancies". Haematologica. 90 (6): 853–4. PMID 15951301.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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 : PER. 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; et al. (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. PMID 17453145.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)