Dual faces of SH2-containing protein-tyrosine phosphatase Shp2/PTPN11 in tumorigenesis

Abstract

PTPN11, which encodes tyrosine phosphatase Shp2, is a critical gene mediating cellular responses to hormones and cytokines. Against original prediction as tumor suppressor for tyrosine phosphatases, PTPN11 was first identified as a proto-oncogene because activating mutations of this gene are associated with leukemogenesis. However, most recent experimental data suggest PTPN11/Shp2 acting as a tumor suppressor in hepatocarcinogenesis. This review focuses on the tumor-promoting or suppressing roles of the gene PTPN11/Shp2 in different cell types.

Keywords

PTPN11/Shp2 / leukemia / hepatocellular carcinoma / mutation

Introduction

Shp2 (previously known as SH-PTP2, SH-PTP3, PTP1D, PTP2C, or Syp) is encoded by PTPN11 gene. Several groups identified Shp2 in the early 1990s as a member of a small subfamily of non-receptor protein tyrosine phosphatases that possess two Src-homology 2 (SH2) domains [1-3]. Shp2 is composed of two tandemly arranged N-terminal SH2 domains (SH2-N and SH2-C), a single catalytic (PTP) domain, and a C-terminal tail with tyrosine phosphorylation sites [4]. The crystal structure of Shp2 indicated that in the basal state, the SH2-N domain interacts with the PTP domain through multiple non-covalent contacts, which leads to auto-inhibition of the catalytic activity [4]. Upon exposure to a variety of extracellular stimuli, the SH2 domains of SHP2 can bind to growth factor receptors such as platelet-derived growth factor (PDGF) receptor as well as to tyrosine-phosphorylated docking proteins, including insulin receptor substrates (IRSs), signal regulatory protein α (SIRPα; also known as SHP substrate-1[SHPS-1]), Grb2-associated binder proteins (Gabs), and fibroblast growth factor receptor substrate (FRS), resulting in the recruitment of Shp2 near the plasma membrane, as well as the increase of the phosphatase activity of Shp2 [5-11].

Given the positive link between protein-tyrosine kinase activation and oncogenesis [12], tyrosine phosphatases were predicted to be tumor suppressors. However, Shp2 was shown to act as a positive signal transducer between receptor protein tyrosine kinases (PTKs) and the Erk pathway in mediating cellular response to hormones and cytokines [13-16]. Consistently, PTPN11 was first identified as a proto-oncogene in leukemia [17]. To add the complexity, most recent findings suggest an unexpected tumor suppressor role of Shp2 in liver cancer [18,19]. This review will focus on the differential roles of Shp2 as both oncogene and tumor suppressor in different cellular contexts.

Shp2 and inherited human diseases

To date, two human genetic disorders, Noonan (OMIM 163950) [20,21] and LEOPARD (OMIM 151100) [22,23] syndromes, have been associated with germline mutations of PTPN11. Mutations in PTPN11 counted for about half of the cases examined in Noonan syndrome. These Noonan syndrome-associated mutations often increase Shp2 phosphatase activity [24,25]. However, the LEOPARD-associated mutations apparently result in reduced phosphatase activity of Shp2 [26,27]. Mouse models with knock-in mutations of both syndromes recapitulated the diseases to certain degrees [28,29]. These disease-causative mutations show the importance of a meticulous regulation of Shp2 phosphatase activity.

Different strategies have been employed to generate Shp2 knockout mice [30-32]. Embryos carrying Shp2 null alleles die around gastrulation (E6.5) [31,32]. However, embryos could survive until mesoderm patterning (E10.5) with truncated alleles [30]. These data suggest that Shp2 has definite roles during embryogenesis. However, the early embryonic lethality has set obstacles to studying the roles of Shp2 in organogenesis and postnatal functions. Therefore, we and others have used different tissue-specific promoter-driven Cre recombinases to create Shp2 deletion models in various cell types. These models have unveiled a number of important roles of Shp2, from embryonic stem cell differentiation, neurogenesis, hematopoiesis, to metabolic regulation [31-37].

PTPN11/Shp2 acts as a proto-oncogene in leukemogenesis

Some patients with Noonan syndrome (around 10%) develop juvenile leukemia [38,39]. Consistently, a mouse model bearing a Noonan syndrome mutation also developed myeloproliferative syndrome [28]. Since the discovery of the association between somatic PTNP11 mutations and Juvenile myelomonocytic leukemia (JMML) [40], critical roles have been unearthed for Shp2 in several types of leukemias [40-43]. Besides the relatively few Noonan syndrome patients with JMML, somatic mutations in PTPN11 account for 34% of non-syndromic JMML, a small percentage of individuals with myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) [40]. Like Noonan syndrome-associated mutations, the somatic mutations in leukemias likely result in upregulation of the phosphatase activity [40,43]. Interestingly, these leukemia-associated mutations are not overlapping with Noonan syndrome-associated mutations [21,40,41]. Compared functionally with Noonan syndrome mutations, these acquired somatic mutations not only exhibit higher phosphatase activities [40], but also are more potent in myeloid transformation of bone marrow cells [44]. However, such mutations cannot be detected in adult patients with myeloid or lymphoid leukemia [42]. Instead, increased expression of Shp2 is present in these samples [42].

Recently, two groups generated inducible knock-in mouse models carrying leukemia-associated Ptpn11 mutations. Functional and mechanistic analyses of these mutants enhanced our understanding of Shp2 hyperactivation and leukemogenesis. Ptpn11^D61Y and Ptpn11^E76K represent two most frequently detected and leukemogenic mutations [17,40,44]. Mice bearing homozygous alleles of either mutation are embryonic lethal [45,46]. Conditional introduction of these two mutations by Mx1-cre [47] leads to fatal myeloproliferative disorder (MPD) similar to JMML in humans [45,46]. Interestingly, Ptpn11^E76K also induced T cell acute lymphoblastic leukemia/lymphoma (T-ALL) and B-ALL, showing leukemogenic effect even in lineage-committed cells. These gain-of-function mutations aberrantly activate hematopoietic stem cells (HSCs) and initiate leukemias [45,46,48]. Indeed, Shp2 is indispensable for embryonic hematopoiesis [49] and also required for maintenance of the HSC and progenitor pool in adult animals [50,51].

The mutations occurring in PTPN11, which confer upregulation of the Shp2 phosphatase, generate oncogenes that favor a proliferative or surviving advantage to cells. Thus, this makes PTPN11 the first proto-oncogene encoding a tyrosine phosphatase in leukemia [17]. Over-activation of the Erk pathway induced by constitutively active Shp2 mutant molecules is likely a major mechanism underlying leukemogenesis. However, Shp2 operates immediately downstream of cell surface receptors and may regulate multiple intracellular signaling pathways. Therefore, alternations in a variety of cell signaling events likely occur in PTPN11/Shp2 knockout or knockdown cells. In most cases, it is difficult to ascertain a causal relationship between a given phenotype and a change in a specific pathway. Increased chromosomal instability was observed in the Shp2^K76D knock-in model, but it is hard to determine which pathway(s) plays a direct role in induction of this event. Profound changes of gene expression profiling have been detected in juvenile phenotypes of leukemia caused by Shp2 gain-of-function mutations, as compared to normal hematopoietic cells. Shp2 has been shown to regulate several signaling routes culminating on control of Kit gene expression via transcription factor Gata2 [50]. Although the majority of Shp2 is distributed in the cytoplasm, the importance of nuclear Shp2 may have been underestimated.

PTPN11/Shp2 acts as a tumor suppressor in liver cancer

Consistent to a positive role of Shp2 in promoting Erk signal, selective deletion of Shp2 in hepatocytes (Shp2^{hep - / -} ) led to impaired regenerative capacity after 70% partial hepatectomy (PHx) in mice [52]. However, these Shp2^{hep - / -} mutants developed spontaneously macroscopic adenomas when they were older than one year of age, suggesting a tumor suppressor role of Ptpn11 [18]. These seemingly contradictory results suggest that Shp2 can function quite differently in response to acute and chronic liver damages. Indeed, regenerative foci and nodular regenerative hyperplasia progressively developed in the Shp2^{hep - / -} livers early in life [18]. The chronic regeneration in Shp2^{hep - / -} livers can be marked by enhanced incorporation of bromodeoxyuridine (BrdU). In contrast, a sharp reduction of BrdU incorporation in the Shp2^{hep - / -} livers was observed following liver resection in the PHx model [52]. Basal interleukin-6 (IL-6) level was modestly elevated in Shp2^{hep - / -} animals [18], but was dramatically increased after PHx [52]. This increase in basal IL-6 contents and the phosphorylation of its downstream effector Stat3 are in line with the chronic liver damage observed in Shp2^{hep - / -} livers such as peri-portal fibrosis, inflammatory infiltration and necrosis [18]. Although IL-6 is required for restoration of acute liver loss and acts to enhance liver regeneration in mice [53,54], a definitive role of IL-6 for liver regeneration and hepatocarcinogenesis is yet to be established in the Shp2^{hep - / -} mouse model. Hepatocyte-specific ablation of Shp2 also drastically enhances liver tumor development in mice following injection of chemical carcinogen diethylnitrosamine (DEN), reinforcing the tumor-suppressing function of Shp2 in the liver. However, combined deletion of Shp2 and Stat3 decreased tumor development, suggesting that upregulated IL-6/Stat3 signaling is responsible for augmented liver tumorigenesis in the absence of Shp2 [18]. Decreased Shp2 expression was detected in a subfraction of human HCC patient samples [18]. In a larger cohort, even a higher percentage of lower Shp2 expression was identified in a recent study [19]. Although it remains to be determined a causative role of Shp2 deficiency in human HCCs, these clinical data suggest that loss of Shp2 function is likely a promoting factor in hepatocarcinogenesis [18,19].

The underlying mechanisms for the “paradoxical” pro-leukemogenic and anti-HCC effects of Shp2 are not fully understood. Unlike cells in the hematopietic system, hepatocytes have relatively low turnover rates, with different expression profiles of cell cycle-related genes. However, Shp2 acts to mediate pro-survival and mitogenic signals in both systems [18,50]. It is certainly easy to understand that dominantly activating Ptpn11/Shp2 mutations induce leukemogenesis, based on their enhancement of cellular responses to hormones and other extracellular signals. Loss of Shp2 suppressed self-renewal of normal HSCs and maintenance of the HSC/progenitor pool, thus preventing development of leukemia [50].

The anti-tumor effect of Shp2 in the liver is, at first glance, at odds with its leukemia-promoting role. However, this unexpected role of Shp2 in HCC development may be also explained by its positive role in mediating pro-survival signal. Along this line, removal of Shp2 in hepatocytes causes chronic hepatic damage and injury, which triggers inflammation and compensatory hepatocyte proliferation. All this promotes tumorigenesis in the liver, after a long latent period of time. The underlying molecular and cellular mechanisms for the anti-oncogenic effect of Shp2 in the liver is not fully understood, with a lot of questions remaining to be addressed [55]. Accumulation of additional mutations is definitely required for hepatocyte transformation, and indeed DEN-induced tumors usually have increased chromosomal instability [56]. It will also be interesting to determine whether gain-of-function mutations or overexpression of Shp2 in hepatocytes can also cause or enhance hepatocarcinogenesis.

Summary

Against the conventional view on tyrosine phosphatases, PTPN11 was first identified as a proto-oncogene, due to the activating mutations found in leukemia. However, loss of Shp2 promotes hepatocellular carcinoma, suggesting that PTPN11 also functions as a tumor suppressor. These opposing functions of the same gene are dependent on cellular context. Elucidating the dual roles of PTPN11/Shp2 in tumorigenesis may lead to better understanding of tyrosine phosphorylation in cell transformation.

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