Cutting Edge: Association with IκB Kinase β Regulates the Subcellular Localization of Homer3

Yatherajam, Gayatri; Banerjee, Pinaki P.; McCorkell, Kelly A.; Solt, Laura A.; Hanson, Eric P.; Madge, Lisa A.; Kang, Shin-Hyoung; Worley, Paul F.; May, Michael J.

doi:10.4049/jimmunol.0903488

Cited by 7 publications

(6 citation statements)

References 19 publications

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“…Certain gene, such as FHL2 even acts as a positive regulator of transcriptional factor NF-κB activity to promote cell regeneration (41). Here, we only showed the deregulation of gene expression levels by either E 2 or 4-OHT, whereas alteration of subcellular localization of some adaptor protein may have differential biological functions (39, 42). Furthermore, some important signal transduction molecules are activated, as seen by expressing higher serine/threonine (Akt) or tyrosine (c-Src) kinase activity, but without alteration of the amount (11, 43).…”

Section: Discussionmentioning

confidence: 67%

Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells

Fan

Cunliffe

Agboke

et al. 2014

European Journal of Cancer

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Purpose A c-Src inhibitor blocks estrogen (E2)-induced stress and converts E2 responses from inducing apoptosis to growth stimulation in E2-deprived breast cancer cells. A reprogrammed cell line, MCF-7:PF, results in a functional estrogen receptor (ER). We addressed the question of whether the selective ER modulator 4-hydroxytamoxifen (4-OHT) could target ER to prevent E2-stimulated growth in MCF-7:PF cells. Methods Expression of mRNA was measured through real-time RT-PCR. Global gene expression profile was analyzed through microarray. Transcriptome profiles were screened by RNA-sequencing. Results Unexpectedly, both 4-OHT and E2 stimulated cell growth in a concentration-dependent manner. Expression profiling showed a remarkable overlap in genes regulated in the same direction by E2 and 4-OHT. Pathway enrichment analysis of the 280 genes commonly deregulated in MCF-7:PF cells by 4-OHT and E2 revealed functions mainly related to membrane, cytoplasm, and metabolic processes. Further analysis of 98 genes up-regulated by both 4-OHT and E2 uncovered a significant enrichment in genes associated with membrane remodeling, cytoskeleton reorganization, cytoplasmic adapter proteins, cytoplasm organelles proteins, and related processes. 4-OHT was more potent than E2 in up-regulating some membrane remodeling molecules, such as EHD2, FHL2, HOMER3 and RHOF. In contrast, 4-OHT acted as an antagonist to inhibit expression of the majority of enriched membrane-associated genes in wild-type MCF-7 cells. Conclusions Long-term selection pressure has changed the cell population responses to 4-OHT. Membrane-associated signaling is critical for 4-OHT-stimulated cell growth in MCF-7:PF cells. This study provides a rationale for the further investigation of target therapy for tamoxifen resistant patients.

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Section: Discussionmentioning

confidence: 67%

Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells

Fan

Cunliffe

Agboke

et al. 2014

European Journal of Cancer

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“…To date, research on the use of ULD as an interaction module is supported by the following findings: (1) IKKβ ULD binds weakly to its specific substrate IκB (Xu et al, 2011), (2) ULD of human IKKβ alone can associate with Homer 3 coiled-coil/leucine zipper domain (Yatherajam et al, 2010), and (3) TBK1 ULD interacts with its substrate (IRF3) through the IAD domain of IRF3 (Ikeda et al, 2007). Hence, there must exist additional binding surfaces apart from the conserved Ile44 hydrophobic patch described above.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of the ubiquitin-like domain of human TBK1

Miyahira

et al. 2012

Protein Cell

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TANK-binding kinase 1 (TBK1) is an important enzyme in the regulation of cellular antiviral effects. TBK1 regulates the activity of the interferon regulatory factors IRF3 and IRF7, thereby playing a key role in type I interferon (IFN) signaling pathways. The structure of TBK1 consists of an N-terminal kinase domain, a middle ubiquitin-like domain (ULD), and a C-terminal elongated helical domain. It has been reported that the ULD of TBK1 regulates kinase activity, playing an important role in signaling and mediating interactions with other molecules in the IFN pathway. In this study, we present the crystal structure of the ULD of human TBK1 and identify several conserved residues by multiple sequence alignment. We found that a hydrophobic patch in TBK1, containing residues Leu316, Ile353, and Val382, corresponding to the “Ile44 hydrophobic patch” observed in ubiquitin, was conserved in TBK1, IκB kinase epsilon (IKKε/IKKi), IκB kinase alpha (IKKα), and IκB kinase beta (IKKβ). In comparison with the structure of the IKKβ ULD domain of Xenopus laevis, we speculate that the Ile44 hydrophobic patch of TBK1 is present in an intramolecular binding surface between ULD and the C-terminal elongated helices. The varying surface charge distributions in the ULD domains of IKK and IKK-related kinases may be relevant to their specificity for specific partners.

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“…TCR stimulation alters the T cell actin cytoskeleton, enabling T cell spreading and conjugation with APCs. In Jurkat cells, successful actin remodeling post-TCR stimulation requires BCL10 S138 phosphorylation [38] and IKKβ-Homer3 association at the IS [41] (Figure 1). Interestingly, BCL10 S138 phosphorylation is also required for macrophage Fc receptor-induced actin polymerization, leading to phagosome formation [42].…”

Section: New Developments In the Tcr-to-nf-κb Pathwaymentioning

confidence: 99%

“…Phosphorylation of S138 is unrelated to CARMA1-BCL10-MALT1 mediated NF-κB activation in both T cells and macrophages [38, 42]. Similarly, the IKKβ-Homer3 mediated actin regulation in T cells is also NF-κB independent [41]. The identity of the precise mechanisms that link phospho-BCL10 and Homer3 to actin remains to be determined.…”

Section: New Developments In the Tcr-to-nf-κb Pathwaymentioning

confidence: 99%

A new look at T cell receptor signaling to nuclear factor-κB

Paul

Schaefer

2013

Trends in Immunology

112

105

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Antigen stimulation of TCR signaling to NF-κB is required for T cell proliferation and differentiation of effector cells. The TCR-to-NF-κB pathway is generally viewed as a linear sequence of events in which TCR engagement triggers a cytoplasmic cascade of protein-protein interactions and post-translational modifications, ultimately culminating in the nuclear translocation of NF-κB. However, recent findings suggest a more complex picture in which distinct signalosomes, previously unrecognized proteins, and newly identified regulatory mechanisms play key roles in signal transmission. In this review, we evaluate recent data and suggest areas of future emphasis in the study of this important pathway.

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Cutting Edge: Association with IκB Kinase β Regulates the Subcellular Localization of Homer3

Abstract: Material

Cited by 7 publications

References 19 publications

Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells

Identification of gene regulation patterns underlying both oestrogen- and tamoxifen-stimulated cell growth through global gene expression profiling in breast cancer cells

Crystal structure of the ubiquitin-like domain of human TBK1

A new look at T cell receptor signaling to nuclear factor-κB

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