Protein tyrosine phosphatase, non-receptor type 11 (also named Shp2)
597 amino acids; about 68 kDa
Shp2, the protein encoded by 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. Shp2/PTPN11 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. Shp2/PTPN11 positively controls the activation of the RAS/MAPK cascade induced by several growth factors, and negatively regulates JAK/STAT signaling.
Germline PTPN11 mutations are involved in Noonan syndrome, Noonan-like syndrome and LEOPARD syndrome.
Somatic PTPN11 mutations have been documented in a heterogeneous group of hematologic malignancies and pre-leukemic disorders (juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia), and rarely in certain solid tumors (melanoma, neuroblastoma, lung adenocarcinoma, colon cancer).
The vast majority of mutations are “substitution missense” and affect residues residing at or close to the interface between the N-SH2 and PTP domains. There is a mutation hot spot corresponding to amino acid 76. Both germline and somatic mutations promote PTPN11 gain-of-function by destabilizing the catalytically inactive conformation of the protein, and prolong signal flux through the RAS/MAPK pathway in a ligand-dependent manner.
Defects in PTPN11 are the cause of LEOPARD syndrome. It is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness.
Defects in PTPN11 are the cause of Noonan syndrome type 1 (NS1). Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Mutations in PTPN11 account for more than 50% of the cases. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS1 inheritance is autosomal dominant.
Defects in PTPN11 are a cause of Noonan-like syndrome, also known as Noonan-like/multiple giant cell lesion syndrome. It is an autosomal dominant disorder characterized by Noonan features associates with giant cell lesions of bone and soft tissue.
In solid tumor-derived cell lines, inhibition of Shp2 with small molecule PTP inhibitors (such as NSC-87877), shRNAs or dominant negative mutants can significantly reduce cell proliferation and soft-agar colony formation, indicating that inhibition of Shp2 can suppress cancer cell proliferation and the transformation phenotype. However, the extent of inhibition varies among different cancer cell lines (Scott LM et al. 2010)
References (open access):
Targeting protein tyrosine phosphatases for anticancer drug discovery. Scott LM, Lawrence HR, Sebti SM, LawrenceNJ, Wu J. Curr Pharm Des. 2010 Jun;16(16):1843-62.
Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, Zampino G, Burgt I, Palleschi A, Petrucci TC, Sorcini M, Schoch C, Foa R, Emanuel PD, Gelb BD. Am J Hum Genet. 2006 Feb;78(2):279-90.