Bim Inhibits Autophagy by Recruiting Beclin 1 to Microtubules

Luo, Shouqing; Garcı́a-Arencibia, Moisés; Zhao, Rui; Puri, Claudia; Toh, Pearl Pei Chern; Sadiq, Oana; Rubinsztein, David C.

doi:10.1016/j.molcel.2012.05.040

Cited by 177 publications

(161 citation statements)

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“…BCL2L11 is known to bridge the interaction between BECN1 and the dynein light chain LC8 and thus inhibits autophagy through targeting BECN1 to the cytoskeleton. 35 Nevertheless, phosphorylation of BCL2L11 abrogates binding of LC8 to BCL2L11, causing their disassociation and activation of autophagy. 35 We found that ER stress increased phosphorylation of BCL2L11, which conceivably contributed activation of autophagy by freeing BECN1.…”

Section: Discussionmentioning

confidence: 99%

“…20,30,32 Activation of MAPK8/9 by ER stress also activates autophagy through phosphorylation of prosurvival BCL2 family proteins including BCL2 and BCL2L1/BIM thus dissociating them from BECN1/Beclin 1 that plays a critical part in initiation of autophagy flux. [33][34][35][36] Similarly, the other prosurvival protein MCL1 can also bind to BECN1 and disruption of the association triggers autophagy. 37,38 It seems therefore that ER stress may activate autophagy through varying mechanisms depending on cell types and stimuli in question.…”

Section: Ripk1 (Receptor [Tnfrsf]mentioning

confidence: 99%

“…35 However, phosphorylation of BCL2L11 disassociates the binding thus freeing BECN1 that initiates autophagy. 35 Indeed, associated with the increase in activation of MAPK8/9, BCL2L11 phosphorylation was enhanced in melanoma cells upon induction of ER stress (Fig. 6B), pointing to a role of MAPK8/9 in ER stressinduced BCL2L11 phosphorylation.…”

Section: Mapk8/9 Activation Phosphorylates Bcl2l11 and Disassociates mentioning

confidence: 99%

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RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

et al. 2015

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(2015) RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy, Autophagy, 11:7, 975-994, DOI: 10.1080/15548627.2015 Keywords: autophagy, cell death, endoplasmic reticulum stress, melanoma, RIPK1Abbreviations: 3-MA, 3-methyladenine; AMPK, AMP-activated protein kinase; ATF6, activating transcription factor 6; Baf A1, bafilomycin A 1 ; CAMKK2, calcium/calmodulin-dependent protein kinase kinase 2: b; EIF2AK3/PERK, eukaryotic translation initiation factor 2-a kinase 3; ER, endoplasmic reticulum; ERN1/IRE1, endoplasmic reticulum to nucleus signaling 1; HSF1, heat shock transcription factor 1; HSPA5, heat shock 70kDa protein 5 (glucose-regulated protein: 78kDa); MAP2K1/MEK1, mitogenactivated protein kinase kinase 1; MAPK, mitogen-activated protein kinase; MAPK1/ERK2, mitogen-activated protein kinase 1; MAPK3/ERK1, mitogen-activated protein kinase 3; MAPK8/JNK1, mitogen-activated protein kinase 8; MAPK9/JNK2, mitogenactivated protein kinase 9; MAPK11/p38b, mitogen-activated protein kinase 11; MAPK12/p38g, mitogen-activated protein kinase 12; MAPK13/p38d, mitogen-activated protein kinase 13; MAPK14/p38a, mitogen-activated protein kinase 14; NFKB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; PRKAA1, protein kinase AMP-activated: a 1 catalytic subunit; RIPK1, receptor (TNFRSF)-interacting protein kinase 1; SQSTM1/p62, sequestosome 1; TG, thapsigargin; TM, tunicamycin; TNFRSF1A/ TNFR1, tumor necrosis factor receptor superfamily: member 1A; UPR, unfolded protein response; XBP1, x-box binding protein 1.Although RIPK1 (receptor [TNFRSF]-interacting protein kinase 1) is emerging as a critical determinant of cell fate in response to cellular stress resulting from activation of death receptors and DNA damage, its potential role in cell response to endoplasmic reticulum (ER) stress remains undefined. Here we report that RIPK1 functions as an important prosurvival mechanism in melanoma cells undergoing pharmacological ER stress induced by tunicamycin (TM) or thapsigargin (TG) through activation of autophagy. While treatment with TM or TG upregulated RIPK1 and triggered autophagy in melanoma cells, knockdown of RIPK1 inhibited autophagy and rendered the cells sensitive to killing by TM or TG, recapitulating the effect of inhibition of autophagy. Consistently, overexpression of RIPK1 enhanced induction of autophagy and conferred resistance of melanoma cells to TM-or TG-induced cell death. Activation of MAPK8/JNK1 or MAPK9/JNK2, which phosphorylated BCL2L11/BIM leading to its dissociation from BECN1/Beclin 1, was involved in TM-or TG-induced, RIPK1-mediated activation of autophagy; whereas, activation of the transcription factor HSF1 (heat shock factor protein 1) downstream of the ERN1/IRE1-XBP1 axis of the unfolded protein response was responsible for the increase in RIPK1 in melanoma cells undergoing pharmacological ER stress. Collectively, these results identify upregulation of RIPK1 as an important resistance mechanism of melanoma cells to TM-or TG-induced ...

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Section: Discussionmentioning

confidence: 99%

Section: Ripk1 (Receptor [Tnfrsf]mentioning

confidence: 99%

Section: Mapk8/9 Activation Phosphorylates Bcl2l11 and Disassociates mentioning

confidence: 99%

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RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

et al. 2015

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“…37 This interaction of Bim-EL and LC8 has been more recently shown to also involve binding to Beclin-1, a critical mediator of autophagy. 38 The formation of this Bim-EL-LC8-Beclin-1 complex has been proposed to block the pro-apoptotic activity of Bim-EL by sequestering it away from the mitochondria. Given these data, we hypothesized that ERK-mediated phosphorylation of Bim-EL at S59 in IBC cells could block anoikis by promoting the formation of the Bim-EL-LC8-Beclin-1 complex.…”

Section: Resultsmentioning

confidence: 99%

“…Given that the interaction of Beclin-1 with LC8 and Bim-EL has been shown to prevent Beclin-1 from initiating autophagosome formation, 38 it seems reasonable to speculate that ECMdetached IBC cells are defective in autophagy in addition to anoikis. This presents a unique problem for these cells, as autophagy has previously been shown to be critical for the survival of ECM-detached cells, 46,47 presumably to facilitate nutrient consumption.…”

Section: Discussionmentioning

confidence: 99%

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

et al. 2014

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Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that, in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells.

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Ivermectin as a potential therapeutic strategy for glioma

Hu,

Ju,

Zhang

2023

J of Neuroscience Research

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Ivermectin (IVM), a semi‐synthetic macrolide parasiticide, has demonstrated considerable effectiveness in combating internal and external parasites, particularly nematodes and arthropods. Its remarkable ability to control parasites has earned it significant recognition, culminating in Satoshi Omura and William C. Campbell's receipt of the 2015 Nobel Prize in Physiology or Medicine for their contributions to the development of IVM. In recent years, investigations have revealed that IVM possesses antitumor properties. It can suppress the growth of various cancer cells, including glioma, through a multitude of mechanisms such as selective targeting of tumor‐specific proteins, inducing programmed cell death, and modulation of tumor‐related signaling pathways. Hence, IVM holds tremendous potential as a novel anticancer drug. This review seeks to provide an overview of the underlying mechanisms that enable IVM's capacity to suppress glioma. Furthermore, it aims to elucidate the challenges and prospects associated with utilizing IVM as a new anticancer agent.

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Bim Inhibits Autophagy by Recruiting Beclin 1 to Microtubules

Cited by 177 publications

References 50 publications

RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

RIPK1 regulates survival of human melanoma cells upon endoplasmic reticulum stress through autophagy

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

Ivermectin as a potential therapeutic strategy for glioma

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