TAK1 activation of alpha-TAT1 and microtubule hyperacetylation control AKT signaling and cell growth

Shah, Nirav R.; Kumar, Sanjay; Zaman, Naveed; Pan, Christopher C.; Bloodworth, Jeffrey; W, Lei; Streicher, John M.; Hempel, Nadine; Mythreye, Karthikeyan; Lee, Nam Y.

doi:10.1038/s41467-018-04121-y

Cited by 44 publications

(35 citation statements)

References 35 publications

(37 reference statements)

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“…Images were visualized under the confocal laser‐scanning microscope (Nikon A1R Confocal). The corrected total cell fluorescence (CTCF) was measured in ImageJ according to the following equation: CTCF = Integrated Density − (Area of Selected Cell × Mean Fluorescence of Background Readings) (Shah et al, ).…”

Section: Methodsmentioning

confidence: 99%

Immunoregulatory role of exosomes derived from differentiating mesenchymal stromal cells on inflammation and osteogenesis

Wei

Crawford

et al. 2019

J Tissue Eng Regen Med

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Bone marrow-derived mesenchymal stem/stromal cells (BMSCs) can differentiate into bone-forming osteoblasts, playing a crucial role in bone regeneration. Exosomes are naturally cell-secreted nanovesicles and are lately regraded as an emerging mediator of cellular communication in physiological and pathological conditions. The present study aimed at investigating the complex cellular communications, especially those among the differentiating BMSCs, immune cells (e.g., macrophages), and newly recruited BMSCs via exosome-mediated pathways. Exosomes were first isolated from osteogenically differentiating BMSCs at various stages (Day 0, Day 3, Day 7, and Day 14, respectively). The cellular uptake of isolated exosomes was examined in macrophages and human BMSCs (hBMSCs). The exosomes collected at various osteogenic differentiation stages (0d-exo, 3d-exo, 7d-exo, and 14d-exo) had no effect on the viability of hBMSCs. The uptake of exosomes (0d-exo, 3d-exo, and 7d-exo) significantly decreased proinflammatory-gene expression and the level of an M1 phenotypic marker. Our results then revealed that 3d-exo, 7d-exo, and 14d-exo led to a remarkable increase in mesenchymal stem/stromal cell migration. In addition, 0d-exo significantly promoted the expression of early osteogenic markers, such as alkaline phosphatase and bone morphogenetic protein 2, indicating a pro-osteogenic role of hBMSC-derived exosomes. Collectively, these results suggest that exosomes derived from differentiating mesenchymal stem/stromal cells play a unique osteoimmunomodulatory role in the regulation of bone dynamics.

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Section: Methodsmentioning

confidence: 99%

Immunoregulatory role of exosomes derived from differentiating mesenchymal stromal cells on inflammation and osteogenesis

Wei

Crawford

et al. 2019

J Tissue Eng Regen Med

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“…Akt is another cell signaling molecule that interacts with microtubules (32,33). Akt has been reported to modulate IL-10 expression and GSK-3β activity (30,31).…”

Section: Resultsmentioning

confidence: 99%

“…Akt has been reported to modulate IL-10 expression and GSK-3β activity ( 30 , 31 ). Akt interacts with microtubules, and their interactions are regulated by tubulin acetylation ( 32 , 33 ). HDAC6 modulates a wide range of cellular responses and signaling through deacetylation of tubulin and microtubules ( 25 – 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we investigated HDAC6 regulation of poly (I:C)-induced TBK1 activation, GSK-3β phosphorylation, and IFN-β expression in bone marrow-derived macrophages. Furthermore, AKT, which can modulate IL-10 production and GSK-3β activity (30,31), has been reported to interact with microtubules (32,33). In our studies, we also examined the role of HDAC6 in poly (I:C)-induced AKT phosphorylation and IL-10 production in macrophages.…”

Section: Introductionmentioning

confidence: 93%

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HDAC6 Mediates Poly (I:C)-Induced TBK1 and Akt Phosphorylation in Macrophages

Wang

2020

Front. Immunol.

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Macrophages are derived from monocytes in the bone marrow and play an important role in anti-viral innate immune responses. Macrophages produce cytokines such as interferons and IL-10 upon viral infection to modulate anti-viral immune responses. Type I interferons (IFNs) promote anti-viral defense. IL-10 is a suppressor cytokine that down-regulates anti-viral immune responses. HDAC6 is a tubulin deacetylase that can modulate microtubule dynamics and microtubule-mediated cell signaling pathways. In the present study, we investigated the potential role of HDAC6 in macrophage anti-viral responses by examining poly (I:C)-induced IFN-β and IL-10 production in mouse bone marrow-derived macrophages (BMDMs). We also investigated the role of HDAC6 in poly (I:C)-induced anti-viral signaling such as TBK1, GSK-3β, and Akt activation in mouse BMDMs. Our data showed that HDAC6 deletion enhanced poly (I:C)-induced INF-β expression in macrophages by up-regulating TBK1 activity and eliminating the inhibitory regulation of GSK-3β. Furthermore, HDAC6 deletion inhibited poly (I:C)-induced suppressor cytokine IL-10 production in the BMDMs, which was associated with the inhibition of Akt activation. Our results suggest that HDAC6 modulates IFN-β and IL-10 production in macrophages through its regulation of TBK1, GSK-3β, and Akt signaling. HDAC6 could act as a suppressor of anti-viral innate immune responses in macrophages.

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“…An RNAi screen in Drosophila thus identified proteins involved in the centrosome cycle as regulators of acute insulin-dependent AKT activation [78]. Microtubule acetylation has also recently been linked to sequestration and inhibition of AKT [127]. Further understanding of this intricate crosstalk is required to determine how it may influence or be influenced by oncogenic PIK3CA-induced centrosome amplification.…”

Section: Impact Of Pi3k On Centrosomes (And Vice Versa)mentioning

confidence: 99%

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

Vanhaesebroeck

Bilanges

Madsen

et al. 2019

Preprint

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Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase which opposes class I PI3K signalling. The clinical impact of PI3K inhibitors in solid tumours, aimed at dampening cancercell-intrinsic PI3K activity, has thus far been limited. Challenges include poor drug tolerance, incomplete pathway inhibition and pre-existing or inhibitor-induced resistance. The principle of pharmacologically targeting cancer-cell-intrinsic PI3K activity also assumes that all cancer-promoting effects of PI3K activation are reversible, which might not be the case. Emerging evidence suggests that genetic PI3K pathway activation can induce and/or allow cells to tolerate chromosomal instability, which -even if occurring in a low fraction of the cell population -might help to facilitate and/or drive tumour evolution. While it is clear that such genomic events cannot be reverted pharmacologically, a role for PI3K in the regulation of chromosomal instability could be exploited by using PI3K pathway inhibitors to prevent those genomic events from happening and/or reduce the pace at which they are occurring, thereby dampening cancer development or progression. Such an impact might be most effective in tumours with clonal PI3K activation and achievable at lower drug doses than the maximum-tolerated doses of PI3K inhibitors currently used in the clinic.

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TAK1 activation of alpha-TAT1 and microtubule hyperacetylation control AKT signaling and cell growth

Cited by 44 publications

References 35 publications

Immunoregulatory role of exosomes derived from differentiating mesenchymal stromal cells on inflammation and osteogenesis

Immunoregulatory role of exosomes derived from differentiating mesenchymal stromal cells on inflammation and osteogenesis

HDAC6 Mediates Poly (I:C)-Induced TBK1 and Akt Phosphorylation in Macrophages

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

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