Protein tyrosine phosphatase, non-receptor type 11 (Noonan syndrome 1)
PDB rendering based on 2shp.
Available structures
1aya, 1ayb, 1ayc, 1ayd, 2shp
Identifiers
Symbols	PTPN11; BPTP3; CFC; MGC14433; NS1; PTP-1D; PTP2C; SH-PTP2; SH-PTP3; SHP2
External IDs	OMIM: 176876 MGI: 99511 HomoloGene: 2122
Gene ontology Molecular function • non-membrane spanning protein tyrosine phosphatase activity • protein binding • hydrolase activity Biological process • DNA damage checkpoint • activation of MAPK activity • protein amino acid dephosphorylation • intracellular signaling cascade • axonogenesis • sensory perception of sound • regulation of protein export from nucleus • nerve growth factor receptor signaling pathway
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5781	19247
Ensembl	n/a	ENSMUSG00000043733
UniProt	n/a	Q05C78
RefSeq	NM_002834 (mRNA)	NM_011202 (mRNA)
	NP_002825 (protein)	NP_035332 (protein)
Location	n/a	Chr 5: 121.39 - 121.45 Mb
PubMed search	[1]	[2]

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.^[1]

[edit] 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.

[edit] Genetic diseases associated with PTPN11

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

[edit] 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^[2].

[edit] Leopard syndrome

The mutations that cause Leopard syndrome are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants^[3]. It is currently unclear how mutations that give rise to mutant variants of Shp2 with biochemically opposite characteristics result in similar human genetic syndromes.

[edit] 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, colorectal cancer.^[4] These data suggests that Shp2 may be a proto-oncogene.

[edit] Interactions

PTPN11 has been shown to interact with PLCG2,^[5] Janus kinase 2,^[6][7][8] GAB2,^{[5][9][10][11]} Growth hormone receptor,^[12][13] PTK2B,^[14] CD117,^[15][16] Janus kinase 1,^[6][17] CD31,^{[18][19][20][21]} CEACAM1,^[22] STAT5A,^[23][24] STAT5B,^[23] FRS2,^[25][26][27] Insulin receptor,^[28][29] GAB1,^[30][31] SOCS3,^[17] Glycoprotein 130,^[17][32][33] Insulin-like growth factor 1 receptor,^[34][35] Grb2,^{[36][37][38][6][39][40][27][41][42]} SLAMF1,^[43][44] Epidermal growth factor receptor,^[45][46] PDGFRB,^[47][48] Cbl gene,^[49] SOS1,^[27][50] IRS1^[51][52] and LAIR1.^[53][54]

[edit] References

[edit] Further reading

v • d • e PDB Gallery 1aya: CRYSTAL STRUCTURES OF PEPTIDE COMPLEXES OF THE AMINO-TERMINAL SH2 DOMAIN OF THE SYP TYROSINE PHOSPHATASE   1ayb: CRYSTAL STRUCTURES OF PEPTIDE COMPLEXES OF THE AMINO-TERMINAL SH2 DOMAIN OF THE SYP TYROSINE PHOSPHATASE   1ayc: CRYSTAL STRUCTURES OF PEPTIDE COMPLEXES OF THE AMINO-TERMINAL SH2 DOMAIN OF THE SYP TYROSINE PHOSPHATASE   1ayd: CRYSTAL STRUCTURES OF PEPTIDE COMPLEXES OF THE AMINO-TERMINAL SH2 DOMAIN OF THE SYP TYROSINE PHOSPHATASE   2shp: TYROSINE PHOSPHATASE SHP-2

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