The function of the protein tyrosine phosphatase SHP-1 in cancer

Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worchester, MA 01605, USA.
Gene (Impact Factor: 2.14). 04/2003; 306(1):1-12. DOI: 10.1016/S0378-1119(03)00400-1
Source: PubMed


SHP-1, an SH2 domain-containing protein tyrosine phosphatase, is primarily expressed in hematopoietic cells and behaves as a key regulator controlling intracellular phosphotyrosine levels in lymphocytes. SHP-1 has been proposed as a candidate tumor suppressor gene in lymphoma, leukemia and other cancers, as it functions as an antagonist to the growth-promoting and oncogenic potentials of tyrosine kinase. The decreased levels of SHP-1 protein and SHP-1 mRNA observed in various leukemia and lymphoma cell lines have been attributed to either the methylation of the promoter region of the SHP-1 gene or the post-transcriptional block of SHP-1 protein synthesis. In contrast, SHP-1 protein is normally or over-expressed in some non-lymphocytic cell lines, such as prostate cancer, ovarian cancer and breast cancer cell lines. SHP-1 expression also is decreased in some breast cancer cell lines with negative expression of estrogen receptor as well as some prostate and colorectal cancer cell lines. These data suggest that SHP-1 can play either negative or positive roles in regulating signal transduction pathways. Dysfunction in SHP-1 regulation can cause abnormal cell growth and induce different kinds of cancers. In this paper, we summarize recent studies on the expression and regulation of SHP-1 protein and its pathological function in the development of lymphoma, leukemia and other cancers.

Download full-text


Available from: Lijun Liu, Oct 02, 2014
  • Source
    • "It is tempting to speculate that involvement of SHP-1 in pro-apoptotic accumulation of BimEL may play an important role in prevention of malignant transformation and tumorigenicity of various cell types. This would, indeed, go well with the critical role of SHP-1 in tumour suppression and with the frequently observed down-regulation of SHP-1 in various tumours (Delibrias et al., 1997; Wu et al., 2003; Xiao et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The adenylate cyclase toxin-hemolysin (CyaA, ACT or AC-Hly) plays a key role in virulence of Bordetella pertussis. CyaA penetrates myeloid cells expressing the complement receptor 3 (αM β2 integrin CD11b/CD18) and subverts bactericidal capacities of neutrophils and macrophages by catalyzing unregulated conversion of cytosolic ATP to the key signaling molecule cAMP. We show that the signaling of CyaA-produced cAMP hijacks, by an as yet unknown mechanism, the activity of the tyrosine phosphatase SHP-1 and activates the pro-apoptotic BimEL-Bax cascade. Mitochondrial hyperpolarization occurred in human THP-1 macrophages within 10 minutes of exposure to low CyaA concentrations (e.g. 20 ng ml(-1) ) and was accompanied by accumulation of BimEL and association of the pro-apoptotic factor Bax with mitochondria. BimEL accumulation required cAMP/PKA signaling, depended on SHP-1 activity and was selectively inhibited upon siRNA knockdown of SHP-1 but not of the SHP-2 phosphatase. Moreover, signaling of CyaA-produced cAMP inhibited the AKT/PKB pro-survival cascade, enhancing activity of the FoxO3a transcription factor and inducing Bim transcription. Synergy of FoxO3a activation with SHP-1 hijacking thus enables the toxin to rapidly trigger a persistent accumulation of BimEL, thereby activating the pro-apoptotic program of macrophages and subverting the innate immunity of the host. This article is protected by copyright. All rights reserved.
    Cellular Microbiology 09/2015; DOI:10.1111/cmi.12519 · 4.92 Impact Factor
  • Source
    • "Notably, SHP-1 has tumor-suppressive potential due to its negative regulation of STAT3 oncogenic signaling during tumor progression [7] [8] [9] [10]. It contains two SH2 domains, a catalytic PTP domain, and a C-terminal tail [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: STAT3 activation is associated with poor prognosis in human colorectal cancer (CRC). Our previous data demonstrated that regorafenib (Stivarga) is a pharmacological agonist of SH2 domain-containing phosphatase 1 (SHP-1) that enhances SHP-1 activity and induces apoptosis by targeting STAT3 signals in CRC. This study aimed to find a therapeutic drug that is more effective than regorafenib for CRC treatment. Here, we showed that SC-43 was more effective than regorafenib at inducing apoptosis in vitro and suppressing tumorigenesis in vivo. SC-43 significantly increased SHP-1 activity, downregulated p-STAT3 Tyr705 level, and induced apoptosis in CRC cells. An SHP-1 inhibitor or knockdown of SHP-1 by siRNA both significantly rescued the SC-43–induced apoptosis and decreased p-STAT3 Tyr705 level. Conversely, SHP-1 overexpression increased the effects of SC-43 on apoptosis and p-STAT3 Tyr705 level. These data suggest that SC-43– induced apoptosis mediated through the loss of p-STAT3 Tyr705 was dependent on SHP-1 function. Importantly, SC-43– enhanced SHP-1 activity was because of the docking potential of SC-43, which relieved the autoinhibited N-SH2 domain of SHP-1 and inhibited p-STAT3 Tyr705 signals. Importantly, we observed that a significant negative correlation existed between SHP-1 and p-STAT3 Tyr705 expression in CRC patients (P = .038). Patients with strong SHP-1 and weak p-STAT3 Tyr705 expression had significantly higher overall survival compared with patients with weak SHP-1 and strong p-STAT3 Tyr705 expression (P = .029). In conclusion, SHP-1 is suitable to be a useful prognostic marker and a pharmacological target for CRC treatment. Targeting SHP-1-STAT3 signaling by SC-43 may serve as a promising pharmacotherapy for CRC.
    Neoplasia (New York, N.Y.) 09/2015; 17(9):687-696. DOI:10.1016/j.neo.2015.08.007 · 4.25 Impact Factor
  • Source
    • "SHP-1 is a non-transmembrane PTPase and predominantly expressed in hematopoietic cells [24]. It has been shown to be involved in the negative regulation of JAK/STAT signaling in leukemia and lymphoma [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Persistent activation of signal transducers and activator of transcription 3 (STAT3) has been closely related to growth, survival, proliferation, metastasis, and angiogenesis of various cancer cells, and thus its inhibition can be considered a potential therapeutic strategy. In this study, we investigated the role of bergamottin (BGM) obtained from grapefruit juice in abrogating the constitutive STAT3 activation in multiple myeloma (MM) cells. This suppression was mediated through the inhibition of phosphorylation of Janus-activated kinase (JAK) 1/2 and c-Src. Pervanadate reversed the BGM induced down-regulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase (PTP). Furthermore, BGM induced the expression of the tyrosine phosphatase SHP-1, and gene silencing of the SHP-1 by small interfering RNA abolished the ability of BGM to inhibit STAT3 activation, suggesting a critical role for SHP-1 in the action of BGM. BGM also downregulated the expression of STAT3-regulated gene products such as COX-2, VEGF, Cyclin D1, Survivin, IAP-1, Bcl-2, and Bcl-xl in MM cells. This correlated with induction of substantial apoptosis as indicated by an increase in the sub-G1 cell population and caspase-3 induced PARP cleavage. Also, this agent significantly potentiated the apoptotic effects of bortezomib and thalidomide in MM cells. Overall, these results suggest that BGM is a novel blocker of STAT3 activation pathway thus may have a potential in therapy of MM and other cancers.
    Cancer Letters 08/2014; 354(1). DOI:10.1016/j.canlet.2014.08.002 · 5.62 Impact Factor
Show more