Multisite Phosphorylation of S6K1 Directs a Kinase Phospho-code that Determines Substrate Selection

Arif, Abul; Jia, Jinsheng; Willard, Belinda; Li, Xiaoxia; Fox, Paul L.

doi:10.1016/j.molcel.2018.11.017

Cited by 42 publications

(40 citation statements)

References 82 publications

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“…T421/S424 are part of a cluster of phosphorylation sites in the C-terminal auto-inhibitory domain of p70-S6K (pseudo-substrate inhibition), and their phosphorylation is necessary for S6K activation [ 30 ]. The regulation of phosphorylation at these sites is not fully understood, but kinases including ERK1/2 [ 49 , 50 ], CDK5 [ 51 , 52 ], JNK [ 53 ], and TBK1 [ 54 ] have been shown to target these auto-inhibitory domain sites. Neither JNK nor ERK1/2 were regulated by WNT4 knockdown in our RPPA, and we previously showed JNK is not a target of non-canonical paracrine WNT4 signaling in MM134 cells [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Estrogen Regulation of mTOR Signaling and Mitochondrial Function in Invasive Lobular Carcinoma Cell Lines Requires WNT4

Shackleford

Bordeaux

et al. 2020

Cancers

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Invasive lobular carcinoma of the breast (ILC) is strongly estrogen-driven and represents a unique context for estrogen receptor (ER) signaling. In ILC, ER controls the expression of the Wnt ligand WNT4, which is critical for endocrine response and anti-estrogen resistance. However, signaling mediated by WNT4 is cell type- and tissue-specific, and has not been explored in ILC. We utilized reverse phase protein array (RPPA) to characterize ER and WNT4-driven signaling in ILC cells and identified that WNT4 mediates downstream mTOR signaling via phosphorylation of S6 Kinase. Additionally, ER and WNT4 control levels of MCL-1, which is associated with regulation of mitochondrial function. In this context, WNT4 knockdown led to decreased ATP production and increased mitochondrial fragmentation. WNT4 regulation of both mTOR signaling and MCL-1 were also observed in anti-estrogen resistant models of ILC. We identified that high WNT4 expression is associated with similar mTOR pathway activation in ILC and serous ovarian cancer tumors, suggesting that WNT4 signaling is active in multiple tumor types. The identified downstream pathways offer insight into WNT4 signaling and represent potential targets to overcome anti-estrogen resistance for patients with ILC.

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Section: Discussionmentioning

confidence: 99%

Estrogen Regulation of mTOR Signaling and Mitochondrial Function in Invasive Lobular Carcinoma Cell Lines Requires WNT4

Shackleford

Bordeaux

et al. 2020

Cancers

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“…One interpretation of this discrepancy was that 4EBP1 and S6K1 were activated in mTOR‐independent manner. In fact, phosphorylation of mTOR substrates is subject to mTOR‐independent several kinases and feedback loops 25,26 …”

Section: Discussionmentioning

confidence: 99%

Analysis of mTOR pathway expression in lymphatic malformation and related diseases

Hori

Ozeki

Hirose

et al. 2020

Pathology International

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The mammalian target of rapamycin (mTOR) inhibitor sirolimus is an effective treatment for difficult‐to‐treat lymphatic anomalies. However, little is known about the expression of mTOR pathway components in lymphatic anomalies. Here we investigated the expression pattern of mTOR pathway components and their phosphorylated forms (mTOR, p‐mTOR, 4EBP1, p‐4EBP1, S6K1 and p‐S6K1) in normal lymphatic vessels and lymphatic anomalies using immunohistochemistry. We studied 18 patients of lymphatic anomalies, including lymphatic malformation (LM, n = 14), Kaposiform lymphangiomatosis (KLA, n = 2) and Kaposiform hemangioendothelioma (KHE, n = 2). Normal lymphatic vessels expressed 4EBP1, S6K1 and p‐S6K1, but not p‐4EBP1, mTOR or p‐mTOR. The mTOR was detected in all lymphatic anomalies, whereas its activation form p‐mTOR was detected in half cases of KLA and KHE but not in LM. All lymphatic anomalies expressed S6K1 and its activated form p‐S6K1. The expression of 4EBP1 was also found in all lymphatic anomalies, but its activation was detected in approximately half of them. The activation of mTOR was seen in tumor (KLA and KHE) but not in malformation (LM), whereas the activation of S6K1 and 4EBP1 was seen in all and half of lymphatic anomalies, respectively.

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“…S1). Additionally, there was reduced expression of pS6 [(phosphorylated ribosomal protein S6), a canonical target of mammalian target of rapamycin (mTOR) activation ( 15 )] in pDCs and decreased IκBα—an inhibitor of the signaling of the NF-κβ transcription factor—in myeloid dendritic cells (mDCs) ( Fig. 1, D and E ).…”

Section: Analysis Of Peripheral Blood Leukocytes From Covid-19 Patienmentioning

confidence: 99%

Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans

Arunachalam

Wimmers

Mok

et al. 2020

Science

1,072

124

1,191

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Coronavirus disease 2019 (COVID-19) represents a global crisis, yet major knowledge gaps remain about human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed immune responses in 76 COVID-19 patients and 69 healthy individuals from Hong Kong and Atlanta, Georgia, United States. In the peripheral blood mononuclear cells (PBMCs) of COVID-19 patients, we observed reduced expression of human leukocyte antigen class DR (HLA-DR) and proinflammatory cytokines by myeloid cells as well as impaired mammalian target of rapamycin (mTOR) signaling and interferon-α (IFN-α) production by plasmacytoid dendritic cells. By contrast, we detected enhanced plasma levels of inflammatory mediators—including EN-RAGE, TNFSF14, and oncostatin M—which correlated with disease severity and increased bacterial products in plasma. Single-cell transcriptomics revealed a lack of type I IFNs, reduced HLA-DR in the myeloid cells of patients with severe COVID-19, and transient expression of IFN-stimulated genes. This was consistent with bulk PBMC transcriptomics and transient, low IFN-α levels in plasma during infection. These results reveal mechanisms and potential therapeutic targets for COVID-19.

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Multisite Phosphorylation of S6K1 Directs a Kinase Phospho-code that Determines Substrate Selection

Cited by 42 publications

References 82 publications

Estrogen Regulation of mTOR Signaling and Mitochondrial Function in Invasive Lobular Carcinoma Cell Lines Requires WNT4

Estrogen Regulation of mTOR Signaling and Mitochondrial Function in Invasive Lobular Carcinoma Cell Lines Requires WNT4

Analysis of mTOR pathway expression in lymphatic malformation and related diseases

Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans

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