The Catalytic Activity of the Eukaryotic Initiation Factor-2α Kinase PKR Is Required to Negatively Regulate Stat1 and Stat3 via Activation of the T-cell Protein-tyrosine Phosphatase

Tyrosine phosphorylation of the transcription factors Stat1 and Stat3 is required for them to dimerize, translocate to the nucleus, and induce gene transcription. Nuclear Stat1 and Stat3 are dephosphorylated and deactivated by the T-cell protein-tyrosine phosphatase (TC-PTP), which facilitates the return of both proteins to the cytoplasm. The protein kinase PKR plays an important role in translational control through the modulation of eukaryotic initiation factor-2α phosphorylation. Previous data have implicated PKR in cell signaling via regulation of Stat1 and Stat3, but the molecular mechanisms underlying these events have remained elusive. Using PKR-/- mouse embryonic fibroblasts and a conditionally active form of human PKR, we demonstrate herein that tyrosine (but not serine) phosphorylation of either Stat1 or Stat3 is impaired in cells with activated kinase. This reduction in Stat1 and Stat3 tyrosine phosphorylation by active PKR proceeds through TC-PTP, which is a substrate of the eukaryotic initiation factor-2α kinase both in vitro and in vivo. TC-PTP phosphorylation alone is insufficient to increase its in vivo phosphatase activity unless accompanied by the inhibition of protein synthesis as a result of PKR activation. These data reveal a novel function of PKR as a negative regulator of Stat1 and Stat3 with important implications in cell signaling. Tyrosine phosphorylation of the transcription factors Stat1 and Stat3 is required for them to dimerize, translocate to the nucleus, and induce gene transcription. Nuclear Stat1 and Stat3 are dephosphorylated and deactivated by the T-cell protein-tyrosine phosphatase (TC-PTP), which facilitates the return of both proteins to the cytoplasm. The protein kinase PKR plays an important role in translational control through the modulation of eukaryotic initiation factor-2α phosphorylation. Previous data have implicated PKR in cell signaling via regulation of Stat1 and Stat3, but the molecular mechanisms underlying these events have remained elusive. Using PKR-/- mouse embryonic fibroblasts and a conditionally active form of human PKR, we demonstrate herein that tyrosine (but not serine) phosphorylation of either Stat1 or Stat3 is impaired in cells with activated kinase. This reduction in Stat1 and Stat3 tyrosine phosphorylation by active PKR proceeds through TC-PTP, which is a substrate of the eukaryotic initiation factor-2α kinase both in vitro and in vivo. TC-PTP phosphorylation alone is insufficient to increase its in vivo phosphatase activity unless accompanied by the inhibition of protein synthesis as a result of PKR activation. These data reveal a novel function of PKR as a negative regulator of Stat1 and Stat3 with important implications in cell signaling. The Stat 5The abbreviations used are: Stat, signal transducer and activator of transcription; IFN, interferon; Jak, Janus kinase; IL-6, interleukin 6; SH2, Src homology 2; TC-PTP, T-cell protein-tyrosine phosphatase; PKR, protein kinase double-stranded RNA-dependent; eIF2α, eukaryotic translation initiation factor-2 α-subunit; MEFs, mouse embryonic fibroblasts; wt, wild-type; PERK, PKR-like endoplasmic reticulum kinase; VSV, vesicular stomatitis virus; shRNA, small hairpin RNA; SHP-2, SH2 domain-containing protein-tyrosine phosphatase-2; GST, glutathione S-transferase; mAb, monoclonal antibody; IRF-1, interferon regulatory factor-1; pAb, polyclonal antibody. family of proteins plays a role in many cellular processes, including development, cell growth and proliferation, and apoptotic cell death (1Levy D.E. Darnell Jr., J.E. Nat. Rev. Mol. Cell Biol. 2002; 3: 651-662Crossref PubMed Scopus (2526) Google Scholar, 2Shuai K. Liu B. Nat. Rev. Immunol. 2003; 3: 900-911Crossref PubMed Scopus (1073) Google Scholar). These transcription factors remain latent in the cytoplasm until activated by extracellular signaling proteins, primarily cytokines and growth factors (1Levy D.E. Darnell Jr., J.E. Nat. Rev. Mol. Cell Biol. 2002; 3: 651-662Crossref PubMed Scopus (2526) Google Scholar, 2Shuai K. Liu B. Nat. Rev. Immunol. 2003; 3: 900-911Crossref PubMed Scopus (1073) Google Scholar). Stat1 plays an important role in the cellular response to interferon (IFN) and viral infection and in the regulation of proliferation and apoptosis (1Levy D.E. Darnell Jr., J.E. Nat. Rev. Mol. Cell Biol. 2002; 3: 651-662Crossref PubMed Scopus (2526) Google Scholar). Stat1 knock-out mice are extremely susceptible to infection with viruses and other pathogens, demonstrating the essential role of this transcription factor in innate immunity (3Durbin J.E. Hackenmiller R. Simon M.C. Levy D.E. Cell. 1996; 84: 443-450Abstract Full Text Full Text PDF PubMed Scopus (1304) Google Scholar, 4Meraz M.A. White J.M. Sheehan K.C. Bach E.A. Rodig S.J. Dighe A.S. Kaplan D.H. Riley J.K. Greenlund A.C. Campbell D. Carver-Moore K. DuBois R.N. Clark R. Aguet M. Schreiber R.D. Cell. 1996; 84: 431-442Abstract Full Text Full Text PDF PubMed Scopus (1401) Google Scholar). At the molecular level, IFN treatment leads to Stat1 activation by phosphorylation at Tyr701 mediated by activated Jaks, a family of tyrosine kinases that are associated with the cytoplasmic portions of IFN receptors (1Levy D.E. Darnell Jr., J.E. Nat. Rev. Mol. Cell Biol. 2002; 3: 651-662Crossref PubMed Scopus (2526) Google Scholar). Tyrosine phosphorylation is essential for Stat1 dimerization, nuclear translocation, DNA binding, and gene transcription (1Levy D.E. Darnell Jr., J.E. Nat. Rev. Mol. Cell Biol. 2002; 3: 651-662Crossref PubMed Scopus (2526) Google Scholar). Phosphorylation at Ser727 in the C-terminal domain of Stat1 enhances its transactivation capacity (5Decker T. Kovarik P. Oncogene. 2000; 19: 2628-2637Crossref PubMed Scopus (712) Google Scholar). Stat3, another member of the Stat family, was discovered as a result of its response to interleukin-6 (IL-6) in hepatocytes (6Akira S. Oncogene. 2000; 19: 2607-2611Crossref PubMed Scopus (306) Google Scholar). Stat3 is a major signal transducer downstream of gp130-like receptors, and its activation induces many responses, including proliferation of B-lymphocytes, activation of terminal differentiation and growth arrest in monocytes, and maintenance of the pluripotency of embryonic stem cells (1Levy D.E. Darnell Jr., J.E. Nat. Rev. Mol. Cell Biol. 2002; 3: 651-662Crossref PubMed Scopus (2526) Google Scholar, 6Akira S. Oncogene. 2000; 19: 2607-2611Crossref PubMed Scopus (306) Google Scholar). As with Stat1, Stat3 is tyrosine-phosphorylated at a site close to the C terminus and serine-phosphorylated within the transactivation domain (1Levy D.E. Darnell Jr., J.E. Nat. Rev. Mol. Cell Biol. 2002; 3: 651-662Crossref PubMed Scopus (2526) Google Scholar, 7Levy D.E. Lee C.K. J. Clin. Investig. 2002; 109: 1143-1148Crossref PubMed Scopus (758) Google Scholar). Stat3 knock-out mice exhibit early embryonic lethality, and loss of Stat3 is even lethal in embryonic stem cells; therefore, Stat3 is also required for embryogenesis (6Akira S. Oncogene. 2000; 19: 2607-2611Crossref PubMed Scopus (306) Google Scholar). Although both Stat1 and Stat3 are hyperphosphorylated in numerous cancers (8Yu H. Jove R. Nat. Rev. Cancer. 2004; 4: 97-105Crossref PubMed Scopus (1972) Google Scholar), Stat3 is categorized as a proto-oncogene, whereas Stat1 is generally believed to act as a tumor suppressor (9Bromberg J. J. Clin. Investig. 2002; 109: 1139-1142Crossref PubMed Scopus (755) Google Scholar). The cell has developed numerous mechanisms to regulate both the duration and magnitude of Stat activation so that it can formulate appropriate responses to cytokine stimulation. Phosphorylation of Stats is inhibited by proteins known as SOCS (suppressors of cytokine signaling), which either interfere with activation of Jaks or compete with Stats for binding to cytokine receptors (10Wormald S. Hilton D.J. J. Biol. Chem. 2004; 279: 821-824Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar, 11Kubo M. Hanada T. Yoshimura A. Nat. Immunol. 2003; 4: 1169-1176Crossref PubMed Scopus (544) Google Scholar). Stat activation is also limited by dephosphorylation of upstream signaling components (i.e. receptors and by the SH2 domain-containing K. Liu B. Nat. Rev. Immunol. 2003; 3: 900-911Crossref PubMed Scopus (1073) Google Scholar, S. Hilton D.J. J. Biol. 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The role of PKR is its to the initiation of translation through phosphorylation of the eukaryotic initiation factor-2 at of Scholar, Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). its capacity to regulate protein PKR has as a major of the and of IFN Clin. Rev. PubMed Scopus Google Scholar). that PKR with Stat1, an that is in cells with IFN or double-stranded S. S. H. T. J. PubMed Scopus Google Scholar, J.E. S. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google that PKR both the nuclear function of Stat1 and the of gene transcription in response to S. S. H. T. J. PubMed Scopus Google Scholar). the role of PKR in Stat1 function S. S. H. T. J. PubMed Scopus Google Scholar, J.E. S. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), the molecular events underlying this regulation have remained elusive. mouse embryonic fibroblasts a knock-out of PKR T. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and a conditionally active form of PKR J. K. J. PubMed Scopus Google Scholar, S. S. S. S. Yoshimura A. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar), we demonstrate that PKR Stat1 and that this regulation through activation of TC-PTP, which in the tyrosine phosphorylation of Stat1 and of Stat1 and Stat3 dephosphorylation by TC-PTP is at in by the inhibition of protein synthesis as a result of PKR activation and phosphorylation. data for the of a PKR and TC-PTP with important implications in the regulation of Stat1 and Stat3 signaling. The of these a by viruses to the Cell and cells PKR or as S. S. S. S. Yoshimura A. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). and PKR-/- mice T. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google as J.E. Immunol. 2002; PubMed Scopus Google Scholar). and as A. H. D. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). cells and in with and mouse and mouse an as R. J. PubMed Scopus Google Scholar). in with and cells in with and cytokine cells and with human human or and activated with and PKR-/- in and with vesicular stomatitis as J.E. S. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and for TC-PTP or was by the TC-PTP or the the to the The in which with and the used to cells in the of as J.E. S. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). cells with for and polyclonal and of and PKR and to the with kinase with as substrate as J.E. S. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to was with of phosphatase and at for the was and of phosphatase was to by at with at and and was at and as S. D. M. Yoshimura A. 2004; PubMed Scopus Google Scholar). The cells with monoclonal or TC-PTP was as the antibody. the nucleus, cells with and gene transactivation was the the The Stat1 was and the Stat3 response was a T. of to which was used as an cells with R. J. PubMed Scopus Google or and the Stat1 activity in was as and PKR-/- with and with was to the was to and to of a of human interferon regulatory or the at for by was as S. S. S. S. Yoshimura A. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). and and of Stat proteins as S. S. H. T. J. PubMed Scopus Google Scholar, J.E. S. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was as D. S. J. 2004; PubMed Scopus Google Scholar). the polyclonal Stat1 Stat3 and Stat1 was Cell and Stat1 and was was a J. used at of with or proteins with the to the of the in the of was by Phosphorylation of Stat1 and Stat3 in in an role of PKR Stat1 activity S. S. H. T. J. PubMed Scopus Google Scholar). this by the tyrosine phosphorylation of Stat1 in with a of the domain of PKR T. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and PKR-/- with mouse and protein with the with that Tyr701 phosphorylation of Stat1 was and in PKR-/- cells with cells to tyrosine Ser727 phosphorylation of Stat1 not and PKR-/- with The of Stat1 Tyr701 phosphorylation in PKR-/- cells in cells by was by with a protein also that Stat1 Tyr701 phosphorylation was in PKR-/- in infection of Stat1 Tyr701 phosphorylation was not in with a of PKR Stat1 activation the other Stat3 tyrosine phosphorylation in and PKR-/- to Stat1, phosphorylation of Stat3 in response to was in PKR-/- cells with cells these data that the activity of PKR a negative Stat1 and Stat3 tyrosine phosphorylation. tyrosine phosphorylation is essential for Stat protein function (1Levy D.E. Darnell Jr., J.E. Nat. Rev. Mol. 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Immunol. 2003; 3: 900-911Crossref PubMed Scopus (1073) Google Scholar), we in activation is also by this cells either or with for of by of and with to the we that a of was tyrosine-phosphorylated in cells that activation with activation. of Stat1 Tyrosine Phosphorylation by PKR through a Tyrosine has that tyrosine phosphorylation of Stat1 phosphorylation and that phosphorylation in a of tyrosine-phosphorylated Stat1 P. D. M. T. J. PubMed Scopus Google Scholar). phosphorylation of Stat1 was not by PKR we that the kinase induces the activity of a tyrosine phosphatase for Stat1 for the role of a tyrosine we the of the tyrosine phosphatase Stat1 phosphorylation in cells or that the of Stat1 Tyr701 phosphorylation in both and cells with this was in of cells a increase in Stat1 phosphorylation in the of whereas cells a At of cells with a increase in Stat1 phosphorylation with a increase by These not that a tyrosine phosphatase Stat1 dephosphorylation in cells with activated PKR, but that cells with active PKR are to treatment with a phosphatase Stat1 and Stat3 Tyrosine Phosphorylation by PKR tyrosine for which Stat1 is a substrate are and TC-PTP K. Liu B. Nat. Rev. Immunol. 2003; 3: 900-911Crossref PubMed Scopus (1073) Google Scholar). is a phosphatase that both and tyrosine-phosphorylated Stat1 A.S. Campbell J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), whereas TC-PTP tyrosine-phosphorylated Stat1 and Stat3 J. M. M. M. K. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). these TC-PTP was to phosphorylation of Stat1 was not by activated this we to TC-PTP in cells the TC-PTP, was to the of TC-PTP in cells by to cells a control and and cells used as and Stat1 tyrosine phosphorylation treatment in cells with cells the control in cells the control and Stat1 Tyr701 phosphorylation by was activation of by with cells treatment the in Stat1 Tyr701 phosphorylation was not in cells with TC-PTP a to activation of with The in Stat1 Tyr701 phosphorylation cells with TC-PTP and the control was in cells with in cells with which an of Stat3 phosphorylation in cells to TC-PTP activity also Stat3 phosphorylation. of by the phosphorylation of Stat3 at in control cells as to cells activation with Stat3 phosphorylation in response to was in cells with activated with cells cells in the of activation These demonstrate that the reduction of both Stat1 Tyr701 and Stat3 phosphorylation by activated PKR PKR the and Nuclear of of that the tyrosine phosphorylation and of Stat1 and Stat3 are in the of active PKR, we the of and gene transcription. cells either the control or TC-PTP with the as for that gene transcription was in both cell treatment in the of activation gene transactivation by was by in control cells with activated treatment with cells with TC-PTP to the with in the Stat1 transcription was to the in both cell treatment of control cells with a in Stat3 activity with a in TC-PTP These data that the of Stat1 Tyr701 and Stat3 phosphorylation through TC-PTP the function of both Tyrosine phosphorylation of Stat1 is a for its nuclear 2003; Scholar). to the cellular of Stat1 in response to PKR activation and treatment with cells either the control or TC-PTP with a of and as and for Stat1, whereas the was by Stat1 both nuclear and cytoplasmic which not in cells with to treatment with in the nuclear of Stat1 in both control and the nuclear of Stat1 by was in control but not in that activation of PKR the nuclear of Stat1 in a TC-PTP by the PKR and TC-PTP, we TC-PTP is by PKR in and proteins in the of and the of in protein was by of with in the phosphorylation of both proteins which was the was used also the to a TC-PTP is by in vivo. Cell with and of TC-PTP phosphorylation by cells to the phosphorylation of proteins that with TC-PTP not this we the phosphorylation of TC-PTP by we TC-PTP, we that a of TC-PTP by was to in cells with with cells which is of in cells TC-PTP not PKR is an we the of TC-PTP phosphorylation and that TC-PTP an in not these that activation of PKR leads to TC-PTP phosphorylation in vivo. Phosphorylation of Stat1 Phosphorylation and the inhibition of protein synthesis by activated PKR plays a role in Stat1 tyrosine we Stat1 phosphorylation in in which has with a D. B. Liu R. P. T. S. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). and cells for Stat1 tyrosine phosphorylation treatment with mouse Phosphorylation was in cells with cells of treatment and and and These in Stat1 phosphorylation not as as in PKR-/- that phosphorylation of both TC-PTP and by PKR is required to a increase in Stat1 phosphorylation. the of phosphorylation the activity of Stat1 by cells with an the This as a the of R. J. PubMed Scopus Google Scholar). transcription treatment was in control and cells a was cells or eIF2α, of PKR activation. cells with Stat1 transactivation activity was by with of PKR in cells a in whereas transcription in cells a the This that PKR both Stat1 phosphorylation and activity not through phosphorylation of TC-PTP, but also through phosphorylation of eIF2α, This of a negative role of PKR in Stat1 activation S. S. H. T. J. PubMed Scopus Google Scholar, J.E. S. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and a novel role of the kinase in the via activation of both a conditionally PKR and cells active PKR that Stat1 tyrosine (but not serine) phosphorylation was in the of active PKR and The regulation was for Stat3 tyrosine phosphorylation with and This regulation through to the transactivation of both Stat1 and and Stat3 and the and protein of the Stat1 was in PKR-/- cells in response to treatment The of TC-PTP this the of PKR activation Stat1 and Stat3 tyrosine phosphorylation C and that active PKR not the phosphorylation of the Stat proteins, but of PKR also the phosphorylation of in response to with a role of TC-PTP in the dephosphorylation of A. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of the phosphatase by not Stat1 tyrosine phosphorylation in cells with activated PKR not that TC-PTP is a of of TC-PTP also the nuclear of Stat1 in the of activated PKR Stat1 the and the of cytokine 2003; Scholar, T. J. 2004; PubMed Scopus Google Scholar). not the nuclear of Stat1 proteins, but nuclear as Stat1 dephosphorylated to its by and mechanisms 2003; Scholar, T. J. 2004; PubMed Scopus Google Scholar). data that activation of PKR the dephosphorylation of Stat1, and these in the phosphorylation and nuclear of Stat1 are by in its cells with TC-PTP protein to the in Stat1 activity in control cells activation of the kinase by treatment and the was for Stat3 Although the of TC-PTP is primarily in the nucleus, it can translocate to the cytoplasm in response to including growth and and T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. M.A. T. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). in the cellular of TC-PTP PKR activation not that PKR another of this protein-tyrosine including TC-PTP, a in and regulation of activity T. H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). at the C-terminal of TC-PTP function as an domain activity A. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), and it is that the site of phosphorylation within this domain or a in TC-PTP that its in vitro phosphatase with TC-PTP by PKR in phosphatase activity that phosphorylation but not for TC-PTP activation in vivo. phosphorylation of TC-PTP at a site within the by kinases not its phosphatase activity P. M. M. B. T. J. 2004; PubMed Scopus Google Scholar). of of TC-PTP insufficient to Stat1 phosphorylation in the of activated we the of translation inhibition TC-PTP protein we discovered that TC-PTP is a in PKR activation or treatment with not the role of in Stat phosphorylation that phosphorylation at a in Stat1 phosphorylation and that inhibition of phosphorylation the in a to PKR-/- cells The in phosphorylation we in this the of activated PKR, that PKR the translation of a that the TC-PTP and its Stat the important of PKR and Stat1 in cells viral the of Stat1 by PKR to a is that PKR the duration and of cytokine signaling through the of TC-PTP that activation of PKR in response to viral infection can also by viruses to the response and to the transcription of gene through activation of activation of TC-PTP by PKR to the activity of Stat1, which viral to by a major of the response This is by that Stat1 activation by tyrosine phosphorylation was in cells with PKR-/- cells infection of signaling by activated PKR the to the in which the phosphorylation is viral by PKR at a of PKR-/- mice to and death J.E. Immunol. 2002; PubMed Scopus Google Scholar, S. H. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, S. R. A. J. 2000; PubMed Scopus Google Scholar). This was by an impaired capacity of PKR-/- mice to viral at the translational S. H. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). with these that of signaling in cells can the of viral in response to PKR activation in a that is the cell viral data also to the of in mice with a of the activity of PKR T. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These PKR-/- mice not exhibit growth or T. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google in to Stat1 knock-out mice (3Durbin J.E. Hackenmiller R. Simon M.C. Levy D.E. Cell. 1996; 84: 443-450Abstract Full Text Full Text PDF PubMed Scopus (1304) Google Scholar, 4Meraz M.A. White J.M. Sheehan K.C. Bach E.A. Rodig S.J. Dighe A.S. Kaplan D.H. Riley J.K. Greenlund A.C. Campbell D. Carver-Moore K. DuBois R.N. Clark R. Aguet M. Schreiber R.D. Cell. 1996; 84: 431-442Abstract Full Text Full Text PDF PubMed Scopus (1401) Google Scholar), not to viral T. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the of Stat3, data for a role of PKR in Stat3 activation in growth cells A. M. S. J. PubMed Scopus Google Scholar). this regulation was in a PKR-/- mouse the domain of the kinase J. A. R. A. Aguet M. J. PubMed Scopus Google Scholar). that these mice a active form of PKR that the double-stranded domain D. S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), it activation of Stat3 in these is a of the protein or a of growth factor signaling. Stat3 as an and its phosphorylation is in many of human (8Yu H. Jove R. Nat. Rev. Cancer. 2004; 4: 97-105Crossref PubMed Scopus (1972) Google Scholar). of Stat3 tyrosine phosphorylation by PKR reveal a novel by the activated kinase to the proliferation of cells and to induce the of tumor cells by apoptosis R. B. J. Cell Biol. PubMed Scopus Google Scholar). this we have an that the of the activity of PKR a in the tyrosine phosphorylation of Stat1 and Stat3, and this to a in have also TC-PTP as a novel substrate of PKR and have that activation of TC-PTP as a result of PKR is for the in Stat phosphorylation. The control of this important signaling for J. for and PKR-/- MEFs, T. for the of the R. for human J. for the of and and R. J. for the and with

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