PKCθ-Mediated PDK1 Phosphorylation Enhances T Cell Activation by Increasing PDK1 Stability

Kang, Jung‐Ah; Choi, Hyunwoo; Yang, Taewoo; Cho, Steve K.; Park, Chul–Seung; Park, Sung‐Gyoo

doi:10.14348/molcells.2017.2236

Cited by 7 publications

(3 citation statements)

References 20 publications

(24 reference statements)

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“…9 Phosphoinositide-dependent protein kinase-1 (PDK1) is a member of the atypical glandular cell AGC kinase subfamily that regulates the activities of most atypical glandular cell kinases during different development stages and treatment of cancers. 14,15 PDK1 is proved to be a potential therapeutic target against angiosarcoma cells and is required in the leucine-induced stimulation of the cardiac mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K) pathway. 16,17 Currently, it is widely reported that phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway acts as an essential pathway in the regulation of cell autophagy and apoptosis.…”

mentioning

confidence: 99%

Retracted: microRNA‐145‐3p inhibits non‐small cell lung cancer cell migration and invasion by targeting PDK1 via the mTOR signaling pathway

Chen¹,

Zheng

Cai

et al. 2017

J of Cellular Biochemistry

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The mammalian target of rapamycin (mTOR) pathway is dysregulated in more than 50% of all human malignancies and is a major target in cancer treatment. In this study, we explored the underlying mechanism involving microRNA-145-3p (miR-145-3p) in the development and progression of non-small cell lung cancer (NSCLC) by targeting PDK1 via the mTOR signaling pathway. NSCLC tissues and adjacent normal tissues were obtained from 83 NSCLC patients. miR-145-3p, PDK1, and mTOR levels were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry. Human NSCLC cell lines A549 and H1299 were transfected with miR-145-3p and siPDK1 to confirm the effect of miR-145-3p and PDK1 on NSCLC cells in vitro. Cell growth was evaluated by a CCK8 assay. Cell motility and chemotaxis analysis were determined by the scratch test and chemotaxis assay, respectively. The protein levels of PDK1 and mTOR were measured using the western blotting. Results showed lower level of miR-145-3p and higher levels of PDK1 and mTOR in NSCLC tissues compared to the adjacent normal tissues. In vitro results showed that cell growth, cell motility, and chemotaxis were all inhibited in cells transfected with miR-145-3p and those transfected with siPDK. Additionally, dual luciferase reporter gene assay helped confirmed that PDK1 is a target of miR-145. Finally, levels of PDK1, mTOR, and phosphorylated-mTOR were lower in cells transfected with miR-145-3p as well as those with siPDK1. These findings indicate that miR-145-3p may inhibit cell growth, motility, and chemotaxis in NSCLC by targeting PDK1 through suppressing the mTOR pathway. K E Y W O R D SmicroRNA-145-3p, mTOR pathway, non-small cell lung cancer, PDK1

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mentioning

confidence: 99%

Retracted: microRNA‐145‐3p inhibits non‐small cell lung cancer cell migration and invasion by targeting PDK1 via the mTOR signaling pathway

Chen¹,

Zheng

Cai

et al. 2017

J of Cellular Biochemistry

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“…PDK1 is required for TCR-mediated activation of NF-κB and PKCθ; selective deletion of PDK1 in T cells abrogates activation of NF-κB and PKCθ 98 . Recently, it was shown that PKCθ induces phosphorylation of PDK1 100 , resulting in T cell activation and TCR-induced NF-κB activation [96][97][98][100][101][102] . PKCθ is involved in the activation of NF-κB 103 .…”

Section: The Pkcθ-ikk-nf-κb Pathwaymentioning

confidence: 99%

Recent insights of T cell receptor-mediated signaling pathways for T cell activation and development

et al. 2020

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T cell activation requires extracellular stimulatory signals that are mainly mediated by T cell receptor (TCR) complexes. The TCR recognizes antigens on major histocompatibility complex molecules with the cooperation of CD4 or CD8 coreceptors. After recognition, TCR-induced signaling cascades that propagate signals via various molecules and second messengers are induced. Consequently, many features of T cell-mediated immune responses are determined by these intracellular signaling cascades. Furthermore, differences in the magnitude of TCR signaling direct T cells toward distinct effector linages. Therefore, stringent regulation of T cell activation is crucial for T cell homeostasis and proper immune responses. Dysregulation of TCR signaling can result in anergy or autoimmunity. In this review, we summarize current knowledge on the pathways that govern how the TCR complex transmits signals into cells and the roles of effector molecules that are involved in these pathways.

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“…This kinase is indispensable for T lymphocyte activation. 44,45 Cell-type specific PDK1 deletion revealed that the absence of PDK1 leads to stunted development of all lymphocytes, including T cells, B cells or NK cells. Therefore, targeting PDK1 very likely causes significant side effects from an immune perspective.…”

Section: Introductionmentioning

confidence: 99%

Myeloid deletion of phosphoinositide-dependent kinase-1 enhances NK cell-mediated antitumor immunity by mediating macrophage polarization

Dong

2020

OncoImmunology

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A large number of heterogeneous macrophages can be observed in solid tumor lesions. Classically activated M1 macrophages are a powerful killer of cancer cells. In contrast, tumor-associated macrophages (TAMs) are often referred to as M2 phenotype and usually impair tumor immunity mediated by cytotoxic lymphocytes, natural killer (NK) cells and CD8 + T cells. Therefore, orchestrating M2 to M1 reprogramming will provide a promising approach to tumor immunotherapy. Here we used a PyMTinduced spontaneous breast cancer model in which M2-polarized macrophages were abundant. This M2 phenotype was closely related to tumor progression and immune dysfunction of NK cells and CD8 + T cells. We then found that these TAMs showed increased energy expenditure and over-activation of two kinases, Akt and mammalian target of rapamycin (mTOR). Myeloid inactivation of phosphoinositide-dependent kinase-1 (PDK1), the upstream regulator for Akt and mTOR signaling, significantly reduced excessive metabolic activation of macrophages. Notably, the loss of PDK1 significantly led to regression of breast cancer and prevented lung metastasis. Mechanistically, PDK1 deficiency mainly inhibited the activation of mTOR complex 1 (mTORC1), transforming TAMs into M1 phenotype, thereby reversing tumor-related dysfunction of T cells and NK cells. Therefore, targeting PDK1 may be a new approach for M2 macrophageenriched solid tumor immunotherapy.

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PKCθ-Mediated PDK1 Phosphorylation Enhances T Cell Activation by Increasing PDK1 Stability

Cited by 7 publications

References 20 publications

Retracted: microRNA‐145‐3p inhibits non‐small cell lung cancer cell migration and invasion by targeting PDK1 via the mTOR signaling pathway

Retracted: microRNA‐145‐3p inhibits non‐small cell lung cancer cell migration and invasion by targeting PDK1 via the mTOR signaling pathway

Recent insights of T cell receptor-mediated signaling pathways for T cell activation and development

Myeloid deletion of phosphoinositide-dependent kinase-1 enhances NK cell-mediated antitumor immunity by mediating macrophage polarization

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