Stat3 Activity Is Required for Centrosome Duplication in Chinese Hamster Ovary Cells

Metge, Brandon J.; Ofori-Acquah, Solomon F.; Stevens, Troy; Balczon, Ron

doi:10.1074/jbc.m407094200

Cited by 19 publications

(19 citation statements)

References 39 publications

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“…A variety of JAK2 regulators and substrates, including phosphorylated STAT1, STAT3, and STAT5, SOCS-1, tyrosine kinase Pyk2, Fyn kinase, PI3K, protein phosphatase PTP-BL, and BRCA1, have been detected at the centrosome (77,(84)(85)(86)(87)(88)(89)(90). These observations support the hypothesis that the centrosome serves as a scaffold for JAK2-dependent signal transduction pathways.…”

Section: Discussionsupporting

confidence: 73%

JAK2 Tyrosine Kinase Phosphorylates and Is Negatively Regulated by Centrosomal Protein Ninein

Jay

Hammer

Nestor-Kalinoski

et al. 2015

Molecular and Cellular Biology

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JAK2 is a cytoplasmic tyrosine kinase critical for cytokine signaling. In this study, we have identified a novel centrosome-associated complex containing ninein and JAK2. We have found that active JAK2 localizes around the mother centrioles, where it partly colocalizes with ninein, a protein involved in microtubule (MT) nucleation and anchoring. We demonstrated that JAK2 is an important regulator of centrosome function. Depletion of JAK2 or use of JAK2-null cells causes defects in MT anchoring and increased numbers of cells with mitotic defects; however, MT nucleation is unaffected. We showed that JAK2 directly phosphorylates the N terminus of ninein while the C terminus of ninein inhibits JAK2 kinase activity in vitro. Overexpressed wild-type (WT) or C-terminal (amino acids 1179 to 1931) ninein inhibits JAK2. This ninein-dependent inhibition of JAK2 significantly decreases prolactin-and interferon gamma (IFN-␥)-induced tyrosyl phosphorylation of STAT1 and STAT5. Downregulation of ninein enhances JAK2 activation. These results indicate that JAK2 is a novel member of centrosome-associated complex and that this localization regulates both centrosomal function and JAK2 kinase activity, thus controlling cytokine-activated molecular pathways. JAK2 is a tyrosine kinase that is activated by two-thirds of the cytokine/hematopoietin receptor superfamily. JAK2 activation initiates a variety of downstream signaling events that lead to diverse physiological responses to cytokines, including regulation of body growth, hematopoiesis, satiety, lactation, and various immune functions. Upon activation, receptor-bound JAK2 phosphorylates specific tyrosine residues of its downstream targets, activating cell survival/proliferation-promoting signaling pathways (1). One target of JAK2 is a family of transcription factors termed signal transducers and activators of transcription (STATs). STATs exist within the cytoplasm in a latent or inactive state; they are recruited by cytokine receptor complexes through interaction between the receptor or JAK phosphotyrosines and the Src homology 2 (SH2) domain of the STAT protein. Several additional kinase cascades may be activated by JAK2, including phosphoinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Three mechanisms of JAK2 activation at the genetic level have been implicated in hematologic malignancies: point mutations, translocations, and amplifications (reviewed in reference 2). Mutations within the pseudokinase domain of JAK2 were detected in a spectrum of myeloproliferative diseases. A V617F gain-of-function point mutation is the cause of ϳ90% of all polycythemia vera cases and ϳ50% of all essential thrombocythemia and primitive myelofibrosis cases (3, 4). Several additional mutations leading to constitutively active JAK2 have been identified recently in patients, including a JAK2 K539L mutant. A T875N substitution in JAK2 was also identified in megakaryoblastic myeloid leukemia cells. In a patient with trisomy 21 and B cell precursor acute lymphoblastic l...

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Section: Discussionsupporting

confidence: 73%

JAK2 Tyrosine Kinase Phosphorylates and Is Negatively Regulated by Centrosomal Protein Ninein

Jay

Hammer

Nestor-Kalinoski

et al. 2015

Molecular and Cellular Biology

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“…It regulates G 1 cyclins (D1 and E), is involved in centrosome duplication, and is well-known to be associated with cell survival and cell proliferation, which are two cell processes predominantly affected in MPD (28,46,47). Similarly, a recent report has also pointed to the role of STAT3 in centrosome duplication (48). Downstream targets of AKT and STAT in centrosome regulation remain unidentified.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Tyrosine Kinase of Malignant Hemopathy Targets the Centrosome

et al. 2005

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Myeloproliferative disorders (MPD) are malignant diseases of hematopoietic progenitor cells. Many MPDs result from a chromosomal translocation that creates a fusion gene encoding a chimeric kinase. The fibroblast growth factor receptor 1 (FGFR1)-MPD is characterized by the fusion of the FGFR1 kinase with various partners, including FOP. We show here that both normal FOP and FOP-FGFR1 fusion kinase localize to the centrosome. The fusion kinase encounters substrates at the centrosome where it induces strong phosphorylation on tyrosine residues. Treatment with FGFR1 kinase inhibitor SU5402 abolishes FOP-FGFR1-induced centrosomal phosphorylation and suppresses the proliferative and survival potentials of FOP-FGFR1 Ba/F3 cells. We further show that FOP-FGFR1 allows cells to overcome G 1 arrest. Therefore, the FOP-FGFR1 fusion kinase targets the centrosome, activates signaling pathways at this organelle, and sustains continuous entry in the cell cycle. This could represent a potential new mechanism of oncogenic transformation occurring specifically at the centrosome. (Cancer Res 2005; 65(16): 7231-40)

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“…Indirubin, a potent cyclindependent kinase (Cdk) inhibitor that arrests Jurkat cells in G 1 (28), and piceatannol, a tyrosine kinase inhibitor that prevents Stat3 activation and centrosome duplication (40,64), were tested in HIV-infected Jurkat cells. We observed that treatment of Jurkat cells with these compounds alone did not significantly alter the DNA content profile in uninfected cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Vpr Cytopathicity Independent of G ₂ /M Cell Cycle Arrest in Human Immunodeficiency Virus Type 1-Infected CD4 ⁺ T Cells

Bolton

Lenardo

2007

J Virol

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The mechanism of CD4 ؉ T-cell depletion in human immunodeficiency virus type 1 (HIV-1)-infected individuals remains unknown, although mounting evidence suggests that direct viral cytopathicity contributes to this loss. The HIV-1 Vpr accessory protein causes cell death and arrests cells in the G 2 /M phase; however, the molecular mechanism underlying these properties is not clear. Mutation of hydrophobic residues on the surface of its third alpha-helix disrupted Vpr toxicity, G 2 /M arrest induction, nuclear localization, and self-association, implicating this region in multiple Vpr functions. Cytopathicity by virion-delivered mutant Vpr protein correlated with G 2 /M arrest induction but not nuclear localization or self-association. However, infection with whole virus encoding these Vpr mutants did not abrogate HIV-1-induced cell killing. Rather, mutant Vpr proteins that are impaired for G 2 /M block still prevented infected cell proliferation, and this property correlated with the death of infected cells. Chemical agents that inhibit infected cells from entering G 2 /M also did not reduce HIV-1 cytopathicity. Combined, these data implicate Vpr in HIV-1 killing through a mechanism involving inhibiting cell division but not necessarily in G 2 /M. Thus, the hydrophobic region of the third alpha-helix of Vpr is crucial for mediating G 2 /M arrest, nuclear localization, and self-association but dispensable for HIV-1 cytopathicity due to residual cell proliferation blockade mediated by a separate region of the protein.

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Stat3 Activity Is Required for Centrosome Duplication in Chinese Hamster Ovary Cells

Cited by 19 publications

References 39 publications

JAK2 Tyrosine Kinase Phosphorylates and Is Negatively Regulated by Centrosomal Protein Ninein

JAK2 Tyrosine Kinase Phosphorylates and Is Negatively Regulated by Centrosomal Protein Ninein

Oncogenic Tyrosine Kinase of Malignant Hemopathy Targets the Centrosome

Vpr Cytopathicity Independent of G ₂ /M Cell Cycle Arrest in Human Immunodeficiency Virus Type 1-Infected CD4 ⁺ T Cells

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Stat3 Activity Is Required for Centrosome Duplication in Chinese Hamster Ovary Cells

Cited by 19 publications

References 39 publications

JAK2 Tyrosine Kinase Phosphorylates and Is Negatively Regulated by Centrosomal Protein Ninein

JAK2 Tyrosine Kinase Phosphorylates and Is Negatively Regulated by Centrosomal Protein Ninein

Oncogenic Tyrosine Kinase of Malignant Hemopathy Targets the Centrosome

Vpr Cytopathicity Independent of G 2 /M Cell Cycle Arrest in Human Immunodeficiency Virus Type 1-Infected CD4 + T Cells

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Vpr Cytopathicity Independent of G ₂ /M Cell Cycle Arrest in Human Immunodeficiency Virus Type 1-Infected CD4 ⁺ T Cells