NF-κB p65 transactivation domain is involved in the NF-κB-inducing kinase pathway

Jiang, Xu; Takahashi, Naoko; Ando, Kiichiro; Otsuka, Takanobu; Tetsuka, T.; Okamoto, Takashi

doi:10.1016/s0006-291x(03)00011-1

Cited by 57 publications

(48 citation statements)

References 51 publications

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“…With respect to TNF-␣ stimulation, we did not observe a defect in either IKK1 Ϫ/Ϫ or WT MEFs, suggesting the involvement of kinase(s) other than IKK1 as catalytic responders to TNF-␣. This finding is in agreement with other reports implicating IKK2, casein kinase II, and MSK1 as mediators of RelA/ p65 phosphorylation (22,23,26,27,33,34).…”

Section: Fig 4 Reconstitution With Kinase-proficient (But Not Kinassupporting

confidence: 94%

“…However, irrespective of these differences, it is clear that the phosphorylation of RelA/p65 augments the transactivation potential of the NF-B transcription factor complex. Kinases and their target residues that have been implicated in RelA/p65 modification include protein kinase A (on Ser 276 ) (22,33), MSK1 (on Ser 276 ) (26), casein kinase II (on Ser 529 ) (27), IKK2 (on Ser 536 ) (23), and NIK and IKK1 (on Ser 536 ) (34).…”

mentioning

confidence: 99%

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Human T-cell Lymphotropic Virus Type 1 Tax Induction of Biologically Active NF-κB Requires IκB Kinase-1-mediated Phosphorylation of RelA/p65

O’Mahony

Montaño

Beneden

et al. 2004

Journal of Biological Chemistry

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Section: Fig 4 Reconstitution With Kinase-proficient (But Not Kinassupporting

confidence: 94%

mentioning

confidence: 99%

Human T-cell Lymphotropic Virus Type 1 Tax Induction of Biologically Active NF-κB Requires IκB Kinase-1-mediated Phosphorylation of RelA/p65

O’Mahony

Montaño

Beneden

et al. 2004

Journal of Biological Chemistry

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“…Since IL-1 and LPS signaling to the IKK complex is broadly similar, this difference with LPS where IKK2 has a role (at least in murine embryonic fibroblasts) is somewhat unexpected. There is also evidence for NFB-inducing kinase activating IKK1, which phosphorylates p65 on serine 536 but does not phosphorylate IB␣ (27). This process may be involved in the Btk pathway in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Bruton's Tyrosine Kinase Is Involved in p65-mediated Transactivation and Phosphorylation of p65 on Serine 536 during NFκB Activation by Lipopolysaccharide

Doyle

Jefferies²,

O’Neill³

2005

Journal of Biological Chemistry

131

102

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Bruton's tyrosine kinase (Btk) has recently been shown to participate in the induction of nuclear factor B (NFB)-dependent gene expression by the lipopolysaccharide (LPS) receptor Toll-like receptor-4 (TLR4). In this study we have examined the mechanism whereby Btk participates in this response. Treatment of the murine monocytic cell line Raw264.7 with LFM-A13, a specific Btk inhibitor, blocked LPS-induced NFB-dependent reporter gene expression but not IB␣ degradation. Transient transfection of HEK293 cells with Btk had no effect on NFB-dependent reporter gene expression but strongly promoted transactivation of a reporter gene by a p65-Gal4 fusion protein. IB␣ degradation activated by LPS was intact in macrophages from X-linked immunodeficiency (Xid) mice, which contain inactive Btk. Transfection of cells with a dominant negative form of Btk (BtkK430R) inhibited LPS-driven p65 mediated transactivation. Additionally LFM-A13 impaired phosphorylation of serine 536 on p65 induced by LPS in HEK293-TLR4 cells, and in Xid macrophages this response was impaired. This study therefore reveals a novel function for Btk. It is required for the signaling pathway activated by TLR4, which culminates in phosphorylation of p65 on serine 536 promoting transactivation by NFB.Bruton's tyrosine kinase (Btk) 1 is a member of the Tec family of non-receptor tyrosine kinases and is found in all cells of the hematopoietic lineage except plasma cells and T-cells (1). In B-cells, activation of the B-cell receptor leads to Btk being rapidly recruited to the plasma membrane where it becomes phosphorylated and activated. Btk is required for normal B-cell development (2) and the gene encoding Btk was first identified as the mutated gene in X-linked agammaglobulinemia (XLA) in humans, an immune disease characterized by a lack of circulating B lymphocytes and an absence of Igs of all classes (3). Mutations in the Btk gene also result in the less severe Xlinked immunodeficiency (Xid) in mice. Various mutations have been identified as being responsible for the XLA phenotype, whereas the mutation in Xid mice has been mapped to arginine 28 (R28C) in the PH domain (4). This prevents Btk associating with the membrane, thus inactivating it. The PH domain is important in the process of Btk activation, since it localizes Btk to the membrane through its interaction with phosphatidylinositol triphosphate (PIP 3 ), which is generated by phosphatidylinositol 3-kinase (PI3K).Due to the major phenotype of Btk deficiency being impaired B-cell development and function, the main focus of interest in Btk has centered around the B-cell. However, several studies have provided a more general role for Btk in immune regulation. Studies in Xid peritoneal macrophages have shown reduced responses to lipopolysaccharide (LPS) stimulation, with tumor necrosis factor ␣ (TNF␣) and IL-1␤ production decreased and macrophage effector functions impaired (5). We have shown that Btk is recruited to the LPS receptor Toll-like receptor-4 (TLR4) where it is activated and is required f...

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“…Phosphorylation of p65 can generally potentiate NF-B activation (90). Several kinases that have been implicated in p65 phosphorylation include protein kinase A (Ser-276) (91,92), mitogen-and stressactivated protein kinase-1 (Ser-276) (93), casein kinase II (Ser-529) (94), protein kinase C (Ser-471), phosphatidylinositol 3-kinase/Akt (Ser-536) (95), p90 ribosomal S6 kinase-1 (Ser-536) (96), IKK2 (Ser-536) (64,65,70), NIK, and IKK1(Ser-536) (35,68). TNF-␣ has been shown to induce p65 phosphorylation at Ser-529 via casein kinase II (94), and IKK1 (68) and IKK2 (64,65,70) phosphorylates p65 on Ser-536.…”

Section: Discussionmentioning

confidence: 99%

“…Both IKK1 and IKK2 have been implicated in this process (34,35,66,67,69,70). Recent studies demonstrate that NIK-IKK1 cascade plays a crucial role in p65 phosphorylation (35,68). To address whether TNAP regulates p65 phosphorylation, we performed Western blot analysis of HEK293T cells that either overexpress or have a stable knockdown of TNAP.…”

Section: Tnap Functions Upstream Of Ikk-it Is Well Known That Tnf-␣ Imentioning

confidence: 99%

TNAP, a Novel Repressor of NF-κB-inducing Kinase, Suppresses NF-κB Activation

Hu¹,

Walters³

et al. 2004

Journal of Biological Chemistry

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NF-κB p65 transactivation domain is involved in the NF-κB-inducing kinase pathway

Cited by 57 publications

References 51 publications

Human T-cell Lymphotropic Virus Type 1 Tax Induction of Biologically Active NF-κB Requires IκB Kinase-1-mediated Phosphorylation of RelA/p65

Human T-cell Lymphotropic Virus Type 1 Tax Induction of Biologically Active NF-κB Requires IκB Kinase-1-mediated Phosphorylation of RelA/p65

Bruton's Tyrosine Kinase Is Involved in p65-mediated Transactivation and Phosphorylation of p65 on Serine 536 during NFκB Activation by Lipopolysaccharide

TNAP, a Novel Repressor of NF-κB-inducing Kinase, Suppresses NF-κB Activation

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