PTPN11

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

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.