Tyrosine-Protein Phosphatase Nonreceptor Type 11 (PTPN11)
Synonyms
Historical Background
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
Intramolecular regulation of SHP2 activity. (a) Structure of human SHP2. SHP2 consists of two tandem SH2 domains (N-SH2 and C-SH2), a single protein tyrosine phosphatase (PTP) domain, and a C-terminal hydrophobic tail that includes tyrosine phosphorylation sites. The residue numbers of amino acids that delineate the various domains or correspond to the tyrosine phosphorylation sites (Y542 and Y580) are indicated. (b) Mechanism for regulation of the PTP activity of SHP2. In the basal state, the N-SH2 domain of SHP-2 interacts with the PTP domain (closed form), resulting in autoinhibition of PTP activity. In response to extracellular stimuli, SHP2 binds via its SH2 domains to tyrosine-phosphorylated activators such as growth factor receptors or docking proteins, resulting in its adoption of an open conformation (open form) that is catalytically active
Physiological Roles of SHP2
Regulation of intracellular signaling by SHP2. (a) In response to extracellular stimuli, SHP2 binds via its SH2 domains either to tyrosine-autophosphorylated receptors or to docking proteins that are tyrosine-phosphorylated by activated tyrosine kinases such as receptor tyrosine kinases or Src family tyrosine kinases. Such interactions result in the activation of SHP2 and its consequent promotion of RAS-MAPK activation, leading to cell proliferation, differentiation, or survival. SHP2 also regulates cell adhesion and migration by controlling the RHO activity. (b) YAP/TAZ transcriptional coactivators interact with SHP2 and promote nuclear translocalization of SHP2. In the nucleus, SHP2 dephosphorylates parafibromin. Dephosphorylated parafibromin interacts with β-catenin and induces the expression of WNT-target genes
Examples of physiological roles of SHP2. (a) During the development of central nervous system, SHP2 is required for self-renewing of neural stem cells and controlling cell-fate (SHP2 is known to increase neuron to astrocyte ratio). SHP2 deletion in neural stem cells impaired corticogenesis and cerebellar development. In the postmitotic forebrain neuron, SHP2 regulates synaptic plasticity and thereby controls locomotor activity and memory formation. (b) Hematoxylin-eosin staining of paraffin-embedded sections of the mid-colon from control (Ptpn11fl/fl) or intestinal epithelial cell-specific SHP2 CKO (Ptpn11fl/fl; villin-cre) mice at 3 weeks of age. Epithelial hyperplasia was relatively prominent, and transmural inflammation with crypt abscesses was occasionally observed in SHP2 CKO mice. Inflammatory infiltrates were also present in both the mucosa and submucosa. Scale bar, 100 μm. (c) SHP2 promotes production of absorptive enterocytes and goblet cells and protects against the development of colitis through activation of RAS
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.
Pathological roles of SHP2. (a) The residue numbers of main mutations responsible for NS and JMML are presented. (b) Mutations of SHP2 responsible for NS and JMML (indicated by a star) that result in constitutive activation of SHP2 without growth factor stimulation appear to induce hyper-activation of RAS and development of NS or JMML. (c) Increased abundance of GAB2 in breast cancer might induce hyper-activation of SHP2 and aberrant activation of the RAS-MAPK signaling pathway. (d) CagA is directly injected by H. pylori into gastric epithelial cells and rapidly undergoes tyrosine phosphorylation by Src family tyrosine kinases (SFKs). Tyrosine-phosphorylated CagA recruits SHP2 and thereby promotes aberrant activation of RAS-MAPK signaling pathway, which in turn develops gastric cancer
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).
Summary
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.
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