Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity

Horiguchi, Haruki; Kadomatsu, Tsuyoshi; Kurahashi, Ryoma; Hara, Chiaki; Miyata, Keishi; M, Baba; Osumi, Hironobu; Terada, Kazutoyo; Araki, Kimi; Takai, Toshiyuki; Kamba, Tomomi; Linehan, W. Marston; Moroishi, Toshiro; Oike, Yuichi

doi:10.1101/gad.329417.119

Cited by 15 publications

(20 citation statements)

References 68 publications

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“…Our studies have revealed that nuclear-localized CTR1 plays a role in the growth recovery kinetics of Arabidopsis hypocotyls by increasing EIN3 stability. Given its negative roles in the ethylene response, the CTR1-mediated stimulation of the ethylene response in the nucleus was surprising; however, many proteins have dual functions in signal transduction pathways, and some perform opposite activities in the same biological process [54][55][56][57] . For example, in human memory control, AGAP3, an NMDA receptor-interacting signaling protein, not only enhances the activity of memory formation but also decreases the activity of memory formation, depending on the perception of different signals 54 .…”

Section: Discussionmentioning

confidence: 99%

Ethylene-triggered subcellular trafficking of CTR1 enhances the response to ethylene gas

et al. 2023

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The phytohormone ethylene controls plant growth and stress responses. Ethylene-exposed dark-grown Arabidopsis seedlings exhibit dramatic growth reduction, yet the seedlings rapidly return to the basal growth rate when ethylene gas is removed. However, the underlying mechanism governing this acclimation of dark-grown seedlings to ethylene remains enigmatic. Here, we report that ethylene triggers the translocation of the Raf-like protein kinase CONSTITUTIVE TRIPLE RESPONSE1 (CTR1), a negative regulator of ethylene signaling, from the endoplasmic reticulum to the nucleus. Nuclear-localized CTR1 stabilizes the ETHYLENE-INSENSITIVE3 (EIN3) transcription factor by interacting with and inhibiting EIN3-BINDING F-box (EBF) proteins, thus enhancing the ethylene response and delaying growth recovery. Furthermore, Arabidopsis plants with enhanced nuclear-localized CTR1 exhibited improved tolerance to drought and salinity stress. These findings uncover a mechanism of the ethylene signaling pathway that links the spatiotemporal dynamics of cellular signaling components to physiological responses.

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Section: Discussionmentioning

confidence: 99%

Ethylene-triggered subcellular trafficking of CTR1 enhances the response to ethylene gas

et al. 2023

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“…Our studies have revealed that nuclear-localized CTR1 plays a role in the growth recovery kinetics of Arabidopsis hypocotyls by increasing EIN3 stability via its interaction with EBFs. Given its negative roles in the ethylene response, the CTR1-mediated stimulation of the ethylene response in the nucleus was unforeseen; however, many proteins have dual functions in signal transduction pathways, and some perform opposite activities in the same biological process [37][38][39][40] . For example, in human memory control, AGAP3, an NMDA receptor-interacting signaling protein, not only enhances the activity of memory formation but also decreases the activity of memory formation, depending on the perception of different signals 37 .…”

Section: Discussionmentioning

confidence: 99%

Ethylene-triggered subcellular trafficking of CTR1 enhances the response to ethylene gas

Lee

Seo

Bakshi

et al. 2020

Preprint

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Ethylene gas controls plant growth and stress responses. Ethylene-exposed dark-grown seedlings exhibit a dramatic growth reduction, yet the seedlings rapidly return to the basal growth rate when ethylene gas is removed. However, the underlying mechanism governing this remarkable reversible acclimation of dark-grown seedlings to ethylene remains enigmatic. Here, 5 we report that ethylene triggers the translocation of the Raf-like protein kinase CONSTITUTIVE TRIPLE RESPONSE1 (CTR1), a negative regulator of ethylene signaling, from the endoplasmic reticulum to the nucleus. Nuclear-localized CTR1 inhibits the ETHYLENE-INSENSITIVE3 (EIN3) transcription factor via the EIN3-BINDING F-box Proteins, resulting in rapid suppression of the ethylene response, thus promoting fast growth recovery. These findings uncover a 10 mechanism of the ethylene signaling pathway that links the spatiotemporal dynamics of cellular signaling components to organismal responses. 15 20 25 3 Introduction:The ability of organisms to respond to and integrate environmental signals leading to an appropriate response is critical for optimal growth and development, particularly for plants, which are non-motile. Plants adapt to a wide variety of abiotic stresses, and upon removal of stress, they need to rapidly restore basal cellular homeostasis. One key signal for abiotic stress 5 is the plant hormone ethylene. Ethylene is involved in multiple aspects of growth and development, including fruit ripening, leaf and floral senescence, cell elongation, seed germination, and root hair formation, as well as responses to biotic and abiotic stress 1-3 .Ethylene-mediated stress acclimation includes, but is not limited to, the rapid elongation of rice internodes in response to flooding, drought responses, salt tolerance, heavy metal tolerance, 10 and morphological changes of roots in response to nutrient deficiency 4-8 . How ethylene regulates such remarkable plasticity of plant stress adaptation is poorly understood, however.Extensive molecular genetic studies have elucidated the basic ethylene signaling pathway 2, 9-12 . In the absence of ethylene, the endoplasmic reticulum (ER)-localized ethylene receptors activate the CTR1 protein kinase, which in turn phosphorylates Ethylene-Insensitive 2 15 (EIN2), an ER membrane-localized Nramp homolog that positively regulates ethylene responses. CTR1-mediated phosphorylation of EIN2 leads to its ubiquitination and proteolysis by the 26S proteasome [11][12][13][14][15][16][17][18] . In response to ethylene, the receptors, and hence CTR1, are inactivated, leading to reduced phosphorylation and increased accumulation of EIN2. EIN2 is then proteolytically cleaved, releasing the C-terminal domain (EIN2-CEND) which translocates 20 into the nucleus where it activates the Ethylene-Insensitive 3 (EIN3) and EIN3-Like (EIL) paralogs which function as central transcription factors in ethylene signaling [16][17][18] . EIN2-CEND also associates with the EIN3-Binding F-box 1 (EBF1) and EBF2 mRNAs and represses their translation, thus ...

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“…The retrovirus packaging cell line Platinum‐E (Plat‐E) (RRID:CVCL_B488) (Cell Biolabs Inc., San Diego, CA, USA) was maintained in DMEM supplemented with 10% FCS, 1 μg·mL −1 puromycin, and 10 μg·mL −1 blasticidin. The human renal tubular epithelial cell line HK‐2 (RRID:CVCL_0302) (ATCC, Manassas, VA, USA) harboring HA ‐ PRCC‐TFE3 (HK‐2/HA‐PRCC‐TFE3) [13] was maintained in DMEM/F‐12 supplemented with 10% FCS, 0.8 μg·mL −1 puromycin, and 10 μg·mL −1 blasticidin. All cell lines have been authenticated in the past 3 years by short tandem repeat analysis using the PowerPlex 16 HS System (Promega, Madison, WI, USA).…”

Section: Methodsmentioning

confidence: 99%

ANGPTL2‐mediated epigenetic repression of MHC‐I in tumor cells accelerates tumor immune evasion

et al. 2023

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Loss or downregulation of major histocompatibility complex class I (MHC‐I) contributes to tumor immune evasion. We previously demonstrated that angiopoietin‐like protein 2 (ANGPTL2) promotes tumor progression using a Xp11.2 translocation renal cell carcinoma (tRCC) mouse model. However, molecular mechanisms underlying ANGPTL2 tumor‐promoting activity in the tRCC model remained unclear. Here, we report that ANGPTL2 deficiency in renal tubular epithelial cells slows tumor progression in the tRCC mouse model and promotes activated CD8+ T‐cell infiltration of kidney tissues. We also found that Angptl2‐deficient tumor cells show enhanced interferon γ‐induced expression of MHC‐I and increased susceptibility to CD8+ T‐cell‐mediated anti‐tumor immune responses. Moreover, we provide evidence that the ANGPTL2‐α5β1 integrin pathway accelerates polycomb repressive complex 2‐mediated repression of MHC‐I expression in tumor cells. These findings suggest that ANGPTL2 signaling in tumor cells contributes to tumor immune evasion and that suppressing that signaling in tumor cells could serve as a potential strategy to facilitate tumor elimination by T‐cell‐mediated anti‐tumor immunity.

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Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity

Cited by 15 publications

References 68 publications

Ethylene-triggered subcellular trafficking of CTR1 enhances the response to ethylene gas

Ethylene-triggered subcellular trafficking of CTR1 enhances the response to ethylene gas

Ethylene-triggered subcellular trafficking of CTR1 enhances the response to ethylene gas

ANGPTL2‐mediated epigenetic repression of MHC‐I in tumor cells accelerates tumor immune evasion

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