PTPN11

PTPN11 is a gene encoding the protein tyrosine phosphatase (PTP), Shp2.

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summary_text = 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. [cite web | title = Entrez Gene: PTPN11 protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5781| accessdate = ]

tructure 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 [Roberts AE, et al. Nature Genetics Published online: 3 December 2006] .

Leopard syndrome

The mutations that cause Leopard syndrome are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants [Kontaridis MI, et al: J Biol Chem 2006; 281: 6785-6792. 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. [Bentires-Alj M, et al: Cancer Research 2004; 64: 8816-8820 These data suggests that Shp2 may be a proto-oncogene.

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Marron MB, Hughes DP, McCarthy MJ, "et al." |title=Tie-1 receptor tyrosine kinase endodomain interaction with SHP2: potential signalling mechanisms and roles in angiogenesis. |journal=Adv. Exp. Med. Biol. |volume=476 |issue= |pages= 35–46 |year= 2000 |pmid= 10949653 |doi=
*cite journal | author=Carter-Su C, Rui L, Stofega MR |title=SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone. |journal=Recent Prog. Horm. Res. |volume=55 |issue= |pages= 293–311 |year= 2000 |pmid= 11036942 |doi=
*cite journal | author=Ion A, Tartaglia M, Song X, "et al." |title=Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome. |journal=Hum. Genet. |volume=111 |issue= 4-5 |pages= 421–7 |year= 2002 |pmid= 12384786 |doi= 10.1007/s00439-002-0803-6
*cite journal | author=Hugues L, Cavé H, Philippe N, "et al." |title=Mutations of PTPN11 are rare in adult myeloid malignancies. |journal=Haematologica |volume=90 |issue= 6 |pages= 853–4 |year= 2006 |pmid= 15951301 |doi=
*cite journal | author=Tartaglia M, Gelb BD |title=Germ-line and somatic PTPN11 mutations in human disease. |journal=European journal of medical genetics |volume=48 |issue= 2 |pages= 81–96 |year= 2005 |pmid= 16053901 |doi= 10.1016/j.ejmg.2005.03.001
*cite journal | author=Ogata T, Yoshida R |title=PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. |journal=Pediatric endocrinology reviews : PER |volume=2 |issue= 4 |pages= 669–74 |year= 2006 |pmid= 16208280 |doi=
*cite journal | author=Feng GS |title=Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation. |journal=Cell Res. |volume=17 |issue= 1 |pages= 37–41 |year= 2007 |pmid= 17211446 |doi= 10.1038/sj.cr.7310140
*cite journal | author=Edouard T, Montagner A, Dance M, "et al." |title=How do Shp2 mutations that oppositely influence its biochemical activity result in syndromes with overlapping symptoms? |journal=Cell. Mol. Life Sci. |volume=64 |issue= 13 |pages= 1585–90 |year= 2007 |pmid= 17453145 |doi= 10.1007/s00018-007-6509-0

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