Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Tyrosine-Protein Phosphatase Nonreceptor Type 11 (PTPN11)

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DOI: https://doi.org/10.1007/978-3-319-67199-4_101832
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Synonyms

 BPTP3;  CFC;  NS1;  Protein tyrosine phosphatase 1D;  Protein tyrosine phosphatase 2C;  Protein tyrosine phosphatase-2;  Protein tyrosine phosphatase, nonreceptor type 11;  PTP-1D;  PTP2C;  PTP-2C;  PTPN11;  SHP2;  Shp2;  SHP-2;  SHPTP2;  SH-PTP2;  SH-PTP3;  Tyrosine-protein phosphatase nonreceptor type 11

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

The structure of SHP2 is conserved from Caenorhabditis elegans to human. In humans, SHP2 protein is composed of 593 amino acids, and the primary structure of SHP2 is very similar to SHP1 (also known as PTPN6), which is specifically expressed in the hematopoietic cells. SHP2 contains two tandem Src homology 2 (SH2) domains (N-SH2 and C-SH2 domains) at the N-terminus followed by a single PTP domain carrying the catalytic activity, and a hydrophobic tail with two tyrosine phosphorylation sites at the C-terminus (Fig. 1a). Biochemical and enzymatic studies have revealed that SHP2 possesses only low PTP activity in its basal state. The N-SH2 domain of SHP2 interacts with the PTP domain when the activity of SHP2 is the basal state. Moreover, this intramolecular interaction of SHP2 results in autoinhibition of its PTP activity (Fig. 1b). The crystal structure of SHP2 indeed indicated that the N-SH2 domain interacts with the PTP domain in the basal state (Hof et al. 1998). In contrast, exposure of cells to a variety of extracellular stimuli activates SHP2. In response to extracellular stimuli, SH2 domains of SHP2 bind to tyrosine-phosphorylated growth factor receptors such as platelet-derived growth factor receptor (PDGFR) or to tyrosine-phosphorylated docking proteins such as insulin receptor substrates (IRSs), signal regulatory protein α (SIRPα), GRB2-associated binding proteins (GABs), and fibroblast growth factor receptor substrate (FRS) (Fig. 1b). Consistent with this notion, synthetic phosphopeptides corresponding to the binding sites for the SH2 domains of SHP2 on the PDGFR or IRS-1 were shown to markedly increase the PTP activity of SHP2 in vitro (Lechleider et al. 1993; Sugimoto et al. 1994; Pluskey et al. 1995). These findings suggest that the interaction between the SH2 domains of SHP2 and tyrosine-phosphorylated molecules disrupts the intramolecular interaction of SHP2 and results in activating SHP2 (Fig. 1b). Such interactions are also important for the recruitment of SHP2 to sites near the plasma membrane where potential substrate proteins may be located.
Tyrosine-Protein Phosphatase Nonreceptor Type 11 (PTPN11), Fig. 1

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

SHP2 promotes the activation of RAS, a small GTPase that activates the RAF-MEK-MAPK cascade and consequently induces cell proliferation, differentiation, or survival (Fig. 2a). The first indication of such a role for SHP2 in vertebrates came from studies showing that forced expression of a catalytically inactive mutant of SHP2 prevented activation of the RAS-MAPK signaling pathway in cultured mammalian cells as well as in Xenopus (Milarski and Saltiel 1994; Noguchi et al. 1994; Tang et al. 1995; Yamauchi et al. 1995). Corkscrew (the Drosophila ortholog of SHP2) and Ptp-2 (the Caenorhabditis elegans ortholog of SHP2) were also shown to be implicated as mediators of RAS activation downstream of receptor tyrosine kinases (Allard et al. 1996; Gutch et al. 1998). Growth factor-induced activation of MAPK was also found to be attenuated in fibroblasts from homozygous SHP2 mutant mice (Saxton et al. 1997). These observations thus supported the notion that SHP2 positively regulates cell growth and differentiation by promoting activation of the RAS-MAPK signaling pathway. Studies with mutants of SHP2 also showed that SHP2 regulates receptor tyrosine kinase- or integrin-dependent cell adhesion and migration, at least in part, by RHO. In addition, SHP2 was found to function in a spatially and temporally specific manner as a positive or negative regulator of RHO activity in integrin-mediated cell adhesion and migration (Fig. 2a). Recently, functions of SHP2 in the nucleus are also proposed. YAP/TAZ (Yes-associated protein/transcriptional coactivator with PDZ-binding motif) transcriptional coactivators promote nuclear translocalization of SHP2. In the nucleus, SHP2 dephosphorylates its substrate, parafibromin, which in turn enhances the WNT signaling (Fig. 2b) (Tsutsumi et al. 2013).
Tyrosine-Protein Phosphatase Nonreceptor Type 11 (PTPN11), Fig. 2

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

In vivo studies have also clarified the physiological importance of SHP2. SHP2 is ubiquitously expressed in various tissues and cell types, and homozygous SHP2 mutant mice, in which exon 3 encoding a part of the N-SH2 domain of SHP2 protein was deleted, were found to die in utero as a result of a defect in gastrulation and abnormal mesoderm patterning (Saxton et al. 1997). Further studies on SHP2 null mice, in which SHP2 protein is completely absent, revealed that SHP2 null embryos die peri-implantation due to massive death of embryonic inner cell mass, apoptosis of trophoblastic cells, and failure to produce trophoblast stem cells. The necessity of SHP2 in trophoblastic cell survival by fibroblast growth factor-4-induced activation of RAS-MAPK signaling pathway was also shown (Yang et al. 2006). These findings thus suggest that the SHP2-RAS-MAPK signaling pathway is essential for normal embryonic development of mice. Moreover, many tissue-specific SHP2 conditional knockout (CKO) mice have been developed, and the importance of SHP2 in each tissue of mice has been shown. In the central nervous system, nestin-Cre-induced SHP2 deletion in neural stem cells impaired corticogenesis and cerebellar development (Fig. 3a). In vitro analysis of neural stem cells showed that the absence of SHP2 reduced self-renewing proliferation of neural stem cells and MAPK activation induced by basic fibroblast growth factor stimulation (Ke et al. 2007). Knockdown of SHP2 or forced expression of a constitutively active mutant of SHP2 in mouse cerebrocortical precursor cells demonstrated that SHP2 activity increases the ratio of neurons to astrocytes (Gauthier et al. 2007). In addition to the roles of SHP2 during the development of central nervous system, the studies from CKO mice lacking SHP2 specifically in postmitotic forebrain neurons showed that SHP2 contributes to regulation of MAPK activation and synaptic plasticity in postmitotic forebrain neurons and thereby controls locomotor activity and memory formation (Fig. 3a) (Kusakari et al. 2015). In the heart, muscle-specific SHP2 CKO mice were shown to develop severe dilated cardiomyopathy. MAPK activation induced by a variety of soluble agonists or pressure overload was attenuated in primary cardiomyocytes from muscle-specific SHP2 CKO mice (Kontaridis et al. 2008). In the intestine, intestinal epithelial cell-specific SHP2 CKO mice were shown to develop severe colitis (Fig. 3b) and die as early as 3–4 weeks after birth. In these CKO mice, a number of absorptive enterocytes and goblet cells were reduced, and migration of intestinal epithelial cells was impaired. In addition, the number of absorptive enterocytes and goblet cells as well as the colitis in SHP2 CKO mice was normalized by expression of an activated form of K-RAS in intestinal epithelial cells, suggesting that SHP2 regulates homeostasis of intestinal epithelial cells through activation of RAS (Fig. 3c) (Heuberger et al. 2014; Yamashita et al. 2014). Other SHP2 CKO mice, in which SHP2 are deleted in specific cells such as T cells, hepatocytes, or neural crest cells, have been also developed. Interestingly, phenotypes of these CKO mice have often been correlated with downregulation of RAS-MAPK activity.
Tyrosine-Protein Phosphatase Nonreceptor Type 11 (PTPN11), Fig. 3

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.

Most of the mutations of SHP2 in NS and leukemia are located within or close proximity to the N-SH2 and PTP domains, and these mutations participate directly in the interaction between the N-SH2 domain and the PTP domain (Fig. 4a). Therefore, 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 between the N-SH2 and PTP domains. Indeed, the PTP activity of either NS- or leukemia-associated SHP2 mutants is shown to be greater than that of wild-type SHP2. Moreover, SHP2 mutants associated with sporadic JMML as well as those related to NS-associated JMML are more activated than NS mutants. Cultured mammalian cells, which were expressed with these various SHP2 mutants, caused prolonged MAPK activation when these cells were stimulated with growth factors. In vivo study showed that knock-in mice expressing the NS-associated mutation D61G mimicked human NS or pediatric leukemia (Araki et al. 2004). Furthermore, forced expression of SHP2 mutants (D61V, D61Y, or E76K) in macrophage progenitors increased the basal activity of MAPK and enhanced MAPK activation following granulocyte-macrophage colony-stimulating factor stimulation (Chan et al. 2005). In addition, mast cells derived from bone marrow expressing mutant SHP2 (D61Y or E76K) showed increased basal and IL-3-induced activity of MAPK and Akt or hyperphosphorylation of STAT5 (signal transducer and activator of transcription 5) (Mohi et al. 2005). Together, these various observations indicate that these mutations of PTPN11 that result in constitutive activation of SHP2 appear to induce hyper-activation of RAS and development of NS or JMML (Fig. 4b). In support of the hyper-activation of RAS-MAPK pathway in NS or JMML development, gain-of-function mutations of K-RAS or N-RAS, or a homozygous loss of NF1 (neurofibromatosis type 1, which negatively regulates RAS by its GTPase activity), are associated with NS or sporadic JMML.
Tyrosine-Protein Phosphatase Nonreceptor Type 11 (PTPN11), Fig. 4

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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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular BiologyKobe University Graduate School of MedicineKobeJapan