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      On the role of tyrosine phosphatases as negative regulators of STAT signaling in breast cancers: new findings and future perspectives

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      Author(s): 1 ,
      Publication date (Electronic):
      Journal: Breast Cancer Research : BCR
      Publisher: BioMed Central

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          Abstract

          The increasing importance of signal transducer and activator of transcription 3 (STAT3) expression in human cancers has led several laboratories to examine in detail the expression of one of its major negative regulators in oncogenesis - the T-cell protein tyrosine phosphatase, nonreceptor type 2 (PTPN2). A recent paper by Shields and colleagues points to the associate depletion of PTPN2 in STAT3-positive breast cancers. We examine these findings and reflect on the mechanism of action of PTPN2 and the consequences of its modulation for STAT3 downstream signaling.

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          Identification of a nuclear Stat1 protein tyrosine phosphatase.

          Wei Zhu, L. Hoeve, Amy Fu … (2002)
          Upon interferon (IFN) stimulation, Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to DNA to activate transcription. The activity of Stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (PTP). We have now purified a Stat1 PTP activity from HeLa cell nuclear extract and identified it as TC45, the nuclear isoform of the T-cell PTP (TC-PTP). TC45 can dephosphorylate Stat1 both in vitro and in vivo. Nuclear extracts lacking TC45 fail to dephosphorylate Stat1. Furthermore, the dephosphorylation of IFN-induced tyrosine-phosphorylated Stat1 is defective in TC-PTP-null mouse embryonic fibroblasts (MEFs) and primary thymocytes. Reconstitution of TC-PTP-null MEFs with TC45, but not the endoplasmic reticulum (ER)-associated isoform TC48, rescues the defect in Stat1 dephosphorylation. The dephosphorylation of Stat3, but not Stat5 or Stat6, is also affected in TC-PTP-null cells. Our results identify TC45 as a PTP responsible for the dephosphorylation of Stat1 in the nucleus.
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            Genome-wide RNAi analysis of JAK/STAT signaling components in Drosophila.

            Gyeong-Hun Baeg, Rui Zhou, Norbert Perrimon (2005)
            The cytokine-activated Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway plays an important role in the control of a wide variety of biological processes. When misregulated, JAK/STAT signaling is associated with various human diseases, such as immune disorders and tumorigenesis. To gain insights into the mechanisms by which JAK/STAT signaling participates in these diverse biological responses, we carried out a genome-wide RNA interference (RNAi) screen in cultured Drosophila cells. We identified 121 genes whose double-stranded RNA (dsRNA)-mediated knockdowns affected STAT92E activity. Of the 29 positive regulators, 13 are required for the tyrosine phosphorylation of STAT92E. Furthermore, we found that the Drosophila homologs of RanBP3 and RanBP10 are negative regulators of JAK/STAT signaling through their control of nucleocytoplasmic transport of STAT92E. In addition, we identified a key negative regulator of Drosophila JAK/STAT signaling, protein tyrosine phosphatase PTP61F, and showed that it is a transcriptional target of JAK/STAT signaling, thus revealing a novel negative feedback loop. Our study has uncovered many uncharacterized genes required for different steps of the JAK/STAT signaling pathway.
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              Distinct transcriptional regulatory modules underlie STAT3’s cell type-independent and cell type-specific functions

              Andrew Paul Hutchins, Diego Diez, Yoshiko Takahashi … (2013)
              Transcription factors (TFs) regulate gene expression by binding to short DNA sequence motifs, yet their binding specificities alone cannot explain how certain TFs drive a diversity of biological processes. In order to investigate the factors that control the functions of the pleiotropic TF STAT3, we studied its genome-wide binding patterns in four different cell types: embryonic stem cells, CD4+ T cells, macrophages and AtT-20 cells. We describe for the first time two distinct modes of STAT3 binding. First, a small cell type-independent mode represented by a set of 35 evolutionarily conserved STAT3-binding sites that collectively regulate STAT3’s own functions and cell growth. We show that STAT3 is recruited to sites with E2F1 already pre-bound before STAT3 activation. Second, a series of different transcriptional regulatory modules (TRMs) assemble around STAT3 to drive distinct transcriptional programs in the four cell types. These modules recognize cell type-specific binding sites and are associated with factors particular to each cell type. Our study illustrates the versatility of STAT3 to regulate both universal- and cell type-specific functions by means of distinct TRMs, a mechanism that might be common to other pleiotropic TFs.
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                Author and article information

                Contributors
                Michel L Tremblay
                Journal
                Journal ID (nlm-ta): Breast Cancer Res
                Journal ID (iso-abbrev): Breast Cancer Res
                Title: Breast Cancer Research : BCR
                Publisher: BioMed Central
                ISSN (Print): 1465-5411
                ISSN (Electronic): 1465-542X
                Publication date (Print): 2013
                Publication date (Electronic): 31 July 2013
                Publication date PMC-release: 31 January 2014
                Volume: 15
                Issue: 4
                Page: 312
                Affiliations
                [1 ]Room 613, Cancer Building, McGill University, 1160 Pine Avenue, Montreal, Quebec, Canada H3A 1A3
                Article
                Publisher ID: bcr3437
                DOI: 10.1186/bcr3437
                PMC ID: 3978625
                PubMed ID: 23905670
                SO-VID: 238421a2-9230-4f22-88eb-add2c888f0a8
                Copyright © Copyright © 2013 BioMed Central Ltd
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                Subject: Viewpoint

                ScienceOpen disciplines: Oncology & Radiotherapy
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                ScienceOpen disciplines: Oncology & Radiotherapy

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