Tyrosine-Protein Phosphatase Nonreceptor Type 11 (PTPN11)
Src homology 2-containing protein tyrosine phosphatase (SHP2, also known as PTPN11) is a member of the non-receptor-type protein tyrosine phosphatase (PTP) family and is encoded by PTPN11 gene. In the early 1990s, this PTP was identified on the basis of its sequence similarity to the catalytic domain of known PTPs. PTPs dephosphorylate tyrosine-phosphorylated proteins, which generally promote cellular events such as cell growth, differentiation, migration, adhesion, and apoptosis. Therefore, PTPs are considered to be negative regulators in intracellular signal transductions. However, biochemical and genetic analyses in 1990s showed that SHP2 promotes the activation of RAS-MAPK signaling pathway by receptors for various growth factors and cytokines. From the early 2000s, the mutations of Ptpn11 gene have been found in several human diseases such as Noonan syndrome (NS) and pediatric leukemia. In addition, association of other cancer development with upregulation of SHP2 docking proteins has been shown.
Regulation of the PTP Activity of SHP2
Physiological Roles of SHP2
Pathological Roles of SHP2
PTPN11, which encodes human SHP2, was identified as the susceptibility gene for NS. Indeed, germline mutations of PTPN11 have been found to be present in ∼50% of cases of NS. NS is an autosomal dominant disorder with an estimated prevalence between 1/1000 and 1/2500 live births (Tartaglia et al. 2001; Tartaglia and Gelb 2005). The main clinical features of NS include short stature, facial dysmorphia, and congenital cardiopathy. A small percentage of NS patients also develop two childhood leukemias, juvenile myelomonocytic leukemia (JMML) and acute lymphoblastic leukemia. Furthermore, in addition to the germline mutations of PTPN11, somatic mutations of PTPN11 were found in a substantial proportion of JMML patients without NS and in a small percentage of children with myelodysplastic syndrome, acute myeloid leukemia (AML), or B-precursor acute lymphoblastic leukemia. However, PTPN11 mutations appear to be rare in adult AML.
Although PTPN11 mutations appear to be rare in most solid tumors, increased expression of SHP2 docking proteins promotes cancer development. GRB2-associated binding protein 2 (GAB2) is a pleckstrin homology domain-containing docking protein, which binds and activates SHP2 in response to a variety of cytokines and is important for recruitment of SHP2 to sites near the plasma membrane. The gene of GAB2 is frequently amplified in human breast cancer. Forced expression of GAB2 promotes proliferative activity of MCF10A human mammary cells, and co-expression of GAB2 with an activated form of human EGFR-related 2 (HER2) confers an invasive-like phenotype on these cells (Bentires-Alj et al. 2006). Given that these effects of GAB2 require its binding site for SHP2 and activation of MAPK, an increased abundance of GAB2 might induce hyper-activation of SHP2 and develop breast cancer as a result of aberrant activation of the RAS-MAPK signaling pathway (Fig. 4c). Cytotoxin-associated gene A (CagA), which is expressed in Helicobacter pylori (H. pylori) strain, is also a SHP2 docking protein and implicated in cancer development (Fig. 4d) (Hatakeyama and Higashi 2005). Infection with CagA-positive H. pylori is a risk factor for the development of gastric cancer. CagA is directly injected by H. pylori into gastric epithelial cells and rapidly undergoes tyrosine phosphorylation at its EPIYA motifs by Src family tyrosine kinases. Then, tyrosine-phosphorylated EPIYA motifs of CagA serve as docking sites for SHP2. Indeed, forced expression of CagA promotes MAPK activation in gastric epithelial cells, and CagA-expressing transgenic mice evoke hyperplasia in the stomach. Some of CagA-expressing transgenic mice also develop polyps or adenocarcinomas in the stomach and develop myeloid leukemia phenotypes similar to those of mice transplanted with bone marrow cells expressing leukemia-associated mutants of SHP2. From the above findings, SHP2 has increasingly attracted attention as a potential target of cancer therapies. Recently, SHP099 was identified as a highly potent (IC50 = 0.071 μM) inhibitor of SHP2. SHP099 simultaneously binds to the N-SH2, C-SH2, and PTP domains of SHP2, thus stabilizing SHP2 in autoinhibitory conformation. In vitro study showed that SHP099 suppresses the activity of MAPK and the proliferation of receptor tyrosine kinase-driven cancer cells. SHP099 also has antitumor activity in xenograft models (Chen et al. 2016).
SHP2 (also known as PTPN11) is a member of the non-receptor-type PTP family, which is ubiquitously expressed in various tissues and cell types. SHP2 consists of two tandem SH2 domains (N-SH2 and C-SH2 domains), a single PTP domain, and a hydrophobic tail. In the basal state, the N-SH2 domain interacts with the PTP domain in SHP2. This intramolecular interaction of SHP2 results in autoinhibition of its PTP activity. In contrast, the binding of SHP2 via its SH2 domains to tyrosine-phosphorylated activators such as growth factor receptors or docking proteins disrupts the intramolecular interaction of SHP2 and results in activation of SHP2. Although PTPs are generally thought to be negative regulators in intracellular signal transductions, SHP2 promotes the activation of the RAS-MAPK signaling pathway by receptors for various agonists. Indeed, ablation of SHP2 often downregulates the activity of RAS-MAPK signaling pathway. In vivo studies showed that SHP2 null embryos die peri-implantation. Cell-specific SHP2 CKO mice showed that phenotypes of these mice are often correlated with downregulation of RAS-MAPK activity. In human, PTPN11 (human SHP2 gene) mutations are associated with NS and pediatric leukemia. Most of the mutations of SHP2 in NS and leukemia are located within or close proximity to the N-SH2 and PTP domains, and pathogenesis of NS and leukemia is thought to be related to a loss of autoinhibition of PTP activity resulting from disruption of the intramolecular interaction in the mutant SHP2. PTPN11 mutations appear to be rare in most solid tumors. However, increased expression of SHP2 docking proteins promotes cancer development by hyper-activation of SHP2. Recently, SHP2 is thus attracting the attention as a potential target of cancer therapy.
- Kontaridis MI, Yang W, Bence KK, Cullen D, Wang B, Bodyak N, et al. Deletion of Ptpn11 (Shp2) in cardiomyocytes causes dilated cardiomyopathy via effects on the extracellular signal-regulated kinase/mitogen-activated protein kinase and RhoA signaling pathways. Circulation. 2008;117:1423–35. doi:10.1161/CIRCULATIONAHA.107.728865.PubMedPubMedCentralCrossRefGoogle Scholar
- Lechleider RJ, Sugimoto S, Bennett AM, Kashishian AS, Cooper JA, Shoelson SE, et al. Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor. J Biol Chem. 1993;268:21478–81.PubMedPubMedCentralGoogle Scholar