Protein tyrosine phosphatase SHP-2: A proto-oncogene product that promotes Ras activation

Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
Cancer Science (Impact Factor: 3.52). 07/2009; 100(10):1786-93. DOI: 10.1111/j.1349-7006.2009.01257.x
Source: PubMed


SHP-2 is a cytoplasmic protein tyrosine phosphatase (PTP) that contains two Src homology 2 (SH2) domains. Although PTPs are generally considered to be negative regulators on the basis of their ability to oppose the effects of protein tyrosine kinases, SHP-2 is unusual in that it promotes the activation of the Ras-MAPK signaling pathway by receptors for various growth factors and cytokines. The molecular basis for the activation of SHP-2 is also unique: In the basal state, the NH(2)-terminal SH2 domain of SHP-2 interacts with the PTP domain, resulting in autoinhibition of PTP activity; the binding of SHP-2 via its SH2 domains to tyrosine-phosphorylated growth factor receptors or docking proteins, however, results in disruption of this intramolecular interaction, leading to exposure of the PTP domain and catalytic activation. Indeed, SHP-2 proteins with artificial mutations in the NH(2)-terminal SH2 domain have been shown to act as dominant active mutants in vitro. Such activating mutations of PTPN11 (human SHP-2 gene) were subsequently identified in individuals with Noonan syndrome, a human developmental disorder that is sometimes associated with juvenile myelomonocytic leukemia. Furthermore, somatic mutations of PTPN11 were found to be associated with pediatric leukemia. SHP-2 is also thought to participate in the development of other malignant disorders, but in a manner independent of such activating mutations. Biochemical and functional studies of SHP-2 and genetic analysis of PTPN11 in human disorders have thus converged to provide new insight into the pathogenesis of cancer as well as potential new targets for cancer treatment.

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Available from: Hideki Okazawa, Apr 01, 2015
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    • "BDNF, a member of the neurotrophins family, should bind to and activate tropomyosin related kinase B (TrkB), a receptor tyrosine kinase, to exert its effects (Park and Poo, 2013). SHP2, a Src homology-2 (H2) domain-containing protein tyrosine phosphatase-2, acting as a major regulator of receptor tyrosine kinase (Grossmann et al., 2010), has been implicated in numerous neurotrophin signaling (Case et al., 1994; Matozaki et al., 2009; Ohnishi et al., 1999; Stein-Gerlach et al., 1998), including BDNF/TrkB signaling pathway (Araki et al., 2000; Easton et al., 2006; Neel et al., 2003; Okada et al., 1996). In an in vitro study, Lin and colleagues have reported that SHP2 participates in BDNF-mediated GluN2B-NMDA receptors signaling at the postsynaptic site, and BDNF enhances association of SHP2 with the NMDA receptor subunit GluN2B in the cortical postsynaptic density (PSD) (Lin et al., 1999). "
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    ABSTRACT: The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. Second, we revealed that BDNF induces spinal LTP at C-fiber synapses via functional up-regulation of GluN2B-NMDA receptors in the spinal dorsal horn, and this BDNF-mediated LTP-like state is responsible for the occlusion of spinal LTP elicited by subsequent high-frequency electrical stimulation (HFS) of the sciatic nerve in SNL rats. Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury. Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Disease 11/2014; 73C:428-451. DOI:10.1016/j.nbd.2014.10.025 · 5.08 Impact Factor
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    • "Such binding is important both for activation of the PTP activity of Shp2 as well as for its recruitment to sites near the plasma membrane where potential substrates are located [10], [11]. Although PTPs are generally considered to be negative regulators on the basis of their ability to oppose the effects of PTKs, biochemical and genetic analyses indicate that Shp2 is required for activation of the Ras–mitogen-activated protein kinase (MAPK) signaling pathway operative downstream of the receptors for various growth factors and cytokines, and that it thereby contributes to the promotion of cell proliferation, differentiation, or survival [10], [11]. Moreover, Shp2 is also implicated in the regulation of cell adhesion and migration, in part through its control of the activity of the small GTP-binding protein Rho [12], [13]. "
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    ABSTRACT: Protein tyrosine phosphorylation is thought to be important for regulation of the proliferation, differentiation, and rapid turnover of intestinal epithelial cells (IECs). The role of protein tyrosine phosphatases in such homeostatic regulation of IECs has remained largely unknown, however. Src homology 2-containing protein tyrosine phosphatase (Shp2) is a ubiquitously expressed cytoplasmic protein tyrosine phosphatase that functions as a positive regulator of the Ras-mitogen-activated protein kinase (MAPK) signaling pathway operative downstream of the receptors for various growth factors and cytokines, and it is thereby thought to contribute to the regulation of cell proliferation and differentiation. We now show that mice lacking Shp2 specifically in IECs (Shp2 CKO mice) develop severe colitis and die as early as 3 to 4 weeks after birth. The number of goblet cells in both the small intestine and colon of Shp2 CKO mice was markedly reduced compared with that for control mice. Furthermore, Shp2 CKO mice showed marked impairment of both IEC migration along the crypt-villus axis in the small intestine and the development of intestinal organoids from isolated crypts. The colitis as well as the reduction in the number of goblet cells apparent in Shp2 CKO mice were normalized by expression of an activated form of K-Ras in IECs. Our results thus suggest that Shp2 regulates IEC homeostasis through activation of Ras and thereby protects against the development of colitis.
    PLoS ONE 03/2014; 9(3):e92904. DOI:10.1371/journal.pone.0092904 · 3.23 Impact Factor
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    • "Binding of CD47 to SIRPα is required for the tyrosine phosphorylation of SIRPα [10], which is regulated by various receptor-type tyrosine kinases, including tropomyosin-related kinase B (TrkB), as well as the Src family kinases (SFKs) [4]. When SIRPα is phosphorylated, it then activates Src homology 2 domain–containing protein tyrosine phosphatase (Shp2) [11], [12], which is known to be involved in central nervous system (CNS) cell survival, differentiation, and cellular morphogenesis [13]–[15]. "
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    ABSTRACT: Cluster of differentiation 47 (CD47) is a member of the immunoglobulin superfamily which functions as a ligand for the extracellular region of signal regulatory protein α (SIRPα), a protein which is abundantly expressed in the brain. Previous studies, including ours, have demonstrated that both CD47 and SIRPα fulfill various functions in the central nervous system (CNS), such as the modulation of synaptic transmission and neuronal cell survival. We previously reported that CD47 is involved in the regulation of depression-like behavior of mice in the forced swim test through its modulation of tyrosine phosphorylation of SIRPα. However, other potential behavioral functions of CD47 remain largely unknown. In this study, in an effort to further investigate functional roles of CD47 in the CNS, CD47 knockout (KO) mice and their wild-type littermates were subjected to a battery of behavioral tests. CD47 KO mice displayed decreased prepulse inhibition, while the startle response did not differ between genotypes. The mutants exhibited slightly but significantly decreased sociability and social novelty preference in Crawley's three-chamber social approach test, whereas in social interaction tests in which experimental and stimulus mice have direct contact with each other in a freely moving setting in a novel environment or home cage, there were no significant differences between the genotypes. While previous studies suggested that CD47 regulates fear memory in the inhibitory avoidance test in rodents, our CD47 KO mice exhibited normal fear and spatial memory in the fear conditioning and the Barnes maze tests, respectively. These findings suggest that CD47 is potentially involved in the regulation of sensorimotor gating and social behavior in mice.
    PLoS ONE 02/2014; 9(2):e89584. DOI:10.1371/journal.pone.0089584 · 3.23 Impact Factor
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