Protein kinase PKR is required for platelet-derived growth factor signaling of c-fos gene expression via Erks and Stat3

Deb, Amitabha; Zamanian-Daryoush, Maryam; Xu, Zeyuan; Kadereit, Suzanne; Williams, Bryan R.G.

doi:10.1093/emboj/20.10.2487

Cited by 70 publications

(55 citation statements)

References 73 publications

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“…For instance, PKR mediates heparin-induced SMC antiproliferation through the regulation of STAT1 (10). However, further studies have shown a more complex function in cell proliferation (6,26). Besides the PKR-mediated proproliferation function of TNF, it may also play an important role in platelet-derived growth factor-induced cell proliferation via a different pathway.…”

Section: E521mentioning

confidence: 99%

Inhibition of PKR impairs angiogenesis through a VEGF pathway

Zhu

Zhong

Zhou

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Peripheral artery disease (PAD) is a common clinical problem, and its pathophysiological mechanisms are incompletely understood. Double-stranded RNA-activated protein kinase (PKR) is a ubiquitously expressed serine/threonine protein kinase. Although PKR has been reported in antivirus and the immune system, the role of PKR in vascular function, especially in angiogenesis, is still unclear. PKR−/− mice were used in our experiments. Blood flow recovery was significantly delayed in PKR−/− vs. WT mice (Laser Doppler detection, n = 9, P < 0.01), accompanied by 34% reduced CD31-positive stain in ischemic muscle 28 days after procedure (immunohistochemistry, n = 9, P < 0.05). PKR expression decreased in the first 12 h and increased to peak at 24 h in human umbilical vein endothelial cells (HUVECs) in response to hypoxia (Western blot analyses, n = 3, P < 0.05). Accordingly, phospho-PKR expression increased in HUVECs 24 h after treatment with hypoxia (Western blot analyses, n = 3, P < 0.05). Inhibition of PKR (siRNA transfection) reduced microtubule formation (Matrigel tube formation, n = 3, vs. control siRNA, P < 0.05) and migration (wound healing, n = 3, vs. control siRNA, P < 0.05) by 33 and 59%, respectively. Vascular endothelial growth factor (VEGF) expression in ischemic muscle from PKR−/− mice was significantly decreased by 54% 1 day after procedure ( n = 3, P < 0.05, vs. WT) and by 63% 7 days after procedure ( n = 3, P < 0.01, vs. WT), respectively. At the same time, VEGF expression in HUVECs decreased by 21% ( n = 3, P < 0.05, PKR siRNA vs. control siRNA). These findings demonstrate that PKR mediates angiogenesis through a VEGF pathway, which may form the basis for future intervention of PAD.

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Section: E521mentioning

confidence: 99%

Inhibition of PKR impairs angiogenesis through a VEGF pathway

Zhu

Zhong

Zhou

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…These PKR Ϫ/Ϫ mice do not exhibit growth abnormalities or increased tumorigenesis (20) and, in contrast to Stat1 knock-out mice (3, 4), do not display significant susceptibility to most viral infections (20). In the case of Stat3, previous data provided evidence for a positive role of PKR in Stat3 activation in platelet-derived growth factor-treated cells (42). However, this regulation was described in MEFs from a PKR Ϫ/Ϫ mouse lacking the N-terminal domain of the kinase (43).…”

Section: Discussionmentioning

confidence: 93%

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

Wang

Raven

Baltzis

et al. 2006

Journal of Biological Chemistry

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The Stat 5 family of proteins plays a role in many cellular processes, including development, cell growth and proliferation, and apoptotic cell death (1, 2). These transcription factors remain latent in the cytoplasm until activated by extracellular signaling proteins, primarily cytokines and growth factors (1, 2). Stat1 plays an important role in the cellular response to interferon (IFN) and viral infection and in the regulation of proliferation and apoptosis (1). 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 (3, 4). At the molecular level, IFN treatment leads to Stat1 activation by phosphorylation at Tyr 701 mediated by activated Jaks, a family of tyrosine kinases that are associated with the cytoplasmic portions of IFN receptors (1). Tyrosine phosphorylation is essential for Stat1 dimerization, nuclear translocation, DNA binding, and gene transcription (1). Phosphorylation at Ser 727 in the C-terminal domain of Stat1 enhances its transactivation capacity (5). Stat3, another member of the Stat family, was discovered as a result of its response to interleukin-6 (IL-6) in hepatocytes (6). 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 (1, 6). As with Stat1, Stat3 is tyrosine-phosphorylated at a site close to the C terminus and serine-phosphorylated within the transactivation domain (1, 7). 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 (6). Although both Stat1 and Stat3 are hyperphosphorylated in numerous cancers (8), Stat3 is categorized as a proto-oncogene, whereas Stat1 is generally believed to act as a tumor suppressor (9).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 (10, 11). Stat activation is also limited by dephosphorylation of upstream signaling components (i.e. receptors and Jaks) by the SH2 domain-containing phosphatases (2, 10). In the nucleus, the transcriptional activities of Stats are regulated by PIAS (protein inhibitors of activated Stats), which prevent DNA binding (2), or by specific phosphatases that remove phosphate groups from the tyrosine residues of active Stat molecules (2, 10). In particular, the nuclear T-cell protein-tyrosine phosphatase (TC-PTP) (12) decreases both the cytokine-induced phosphorylation and transcriptional activities of Stat1 and Stat3, thus inhibiting the sig...

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“…It has been proposed that PKR mediates apoptosis at the transcriptional level. For example, PKR signals through STAT1 and STAT3 (36,43,44), interferon regulatory factor 1 (IRF1) (16,45), IRF3 (46), p53 (17,47,48), and the IKK complex to regulate transcription during proinflammatory (16,17,40,45) and/or proapoptotic responses (12,40,45,49). PKR-dependent apoptosis was also associated with Fas-associated death domain (FADD)-mediated activation of caspase 8 (50,51) and up-regulation of Fas and Bax (18,52,53).…”

Section: Discussionmentioning

confidence: 99%

Double-stranded RNA-dependent Protein Kinase Phosphorylation of the α-Subunit of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis

Scheuner

Patel

Wang

et al. 2006

Journal of Biological Chemistry

124

100

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As the molecular processes of complex cell stress signaling pathways are defined, the subsequent challenge is to elucidate how each individual event influences the final biological outcome. Phosphorylation of the translation initiation factor 2 (eIF2␣) at Ser 51 is a molecular signal that inhibits translation in response to activation of any of four diverse eIF2␣ stress kinases. We used gene targeting to replace the wild-type Ser 51 allele with an Ala in the eIF2␣ gene to test the hypothesis that translational control through eIF2␣ phosphorylation is a central death stimulus in eukaryotic cells. Homozygous eIF2␣ mutant mouse embryo fibroblasts were resistant to the apoptotic effects of dsRNA, tumor necrosis factor-␣, and serum deprivation. TNF␣ treatment induced eIF2␣ phosphorylation and activation of caspase 3 primarily through the dsRNA-activated eIF2␣ kinase PKR. In addition, expression of a phospho-mimetic Ser 51 to Asp mutant eIF2␣-activated caspase 3, indicating that eIF2␣ phosphorylation is sufficient to induce apoptosis. The proapoptotic effects of PKR-mediated eIF2␣ phosphorylation contrast with the anti-apoptotic response upon activation of the PKR-related endoplasmic reticulum eIF2␣ kinase, PERK. Therefore, divergent fates of death and survival can be mediated through phosphorylation at the same site within eIF2␣. We propose that eIF2␣ phosphorylation is fundamentally a death signal, yet it may promote either death or survival, depending upon coincident signaling events.

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Protein kinase PKR is required for platelet-derived growth factor signaling of c-fos gene expression via Erks and Stat3

Cited by 70 publications

References 73 publications

Inhibition of PKR impairs angiogenesis through a VEGF pathway

Inhibition of PKR impairs angiogenesis through a VEGF pathway

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

Double-stranded RNA-dependent Protein Kinase Phosphorylation of the α-Subunit of Eukaryotic Translation Initiation Factor 2 Mediates Apoptosis

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