Angiotensin-II and MARCKS

Sartoretto, Juliano L.; Sartoretto, Simone; Michel, Thomas

doi:10.1074/jbc.m112.381517

Cited by 26 publications

(13 citation statements)

References 51 publications

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“…As previously shown (Jin et al 2012;Kalwa et al 2012Kalwa et al , 2014Kalwa and Michel 2011), MARCKS phosphorylation in endothelial cells is reduced by the tyrosine kinase inhibitor bosutinib. Bosutinib also inhibited MARCKS phosphorylation in HT-29 cells (Fig.…”

Section: Role Of Marcks Phosphorylation For Regulation Of Abcb1 Functionsupporting

confidence: 64%

“…Monitoring of fluorescence resonance energy transfer (FRET) biosensors was performed using methods described in detail previously (Aoki et al 2013;Kalwa et al 2012Kalwa et al , 2014Kalwa and Michel 2011). In brief, HT-29 cells were transfected with plasmids encoding FRET biosensors as indicated.…”

Section: Fret Imagingmentioning

confidence: 99%

“…Additionally we could show previously that MARCKS phosphorylation largely depends on the function of the tyrosine kinases c-Abl and Src. We tested compounds related to this signaling pathway and explored the dual c-Abl/Src tyrosine kinase inhibitor bosutinib (SKI606) as a potent blocker of MARCKS phosphorylation (Jin et al 2012;Kalwa et al 2012Kalwa et al , 2014Kalwa and Michel 2011). Thus, beyond the ectopic overexpression of different MARCKS mutants in LoVo cells, the treatment of HT-29 cells with bosutinib provides a tunable system of MARCKS function to analyze the potential crosstalk between ABCB1 and MARCKS in the context of resistance against chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

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Restoration of MARCK enhances chemosensitivity in cancer

Wenzel

Büch

Urban

et al. 2020

J Cancer Res Clin Oncol

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Purpose Increased ATP-binding-cassette (ABC) transporter activity is a major cause of chemotherapy resistance in cancer. The ABC transporter family member ABCB1 is often overexpressed in colorectal cancer (CRC). Phosphatidylinositol-4,5-bisphosphat (PI(4,5)P 2)-dependent pathways are involved in the regulation of ABCB1 function. The protein Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) is a pivotal regulator of PI(4,5)P 2 and inactivated in many CRC cancers via genetic deletion or hyperphosphorylation. Therefore, MARCKS may critically impact ABCB1. Methods CRC samples as well as CRC cell lines were tested for a connection between MARCKS and ABCB1 via immunofluorescence and Western-blot analysis. ABCB1 function was studied via calcein influx assay under treatment with known ABCB1 inhibitors (verapamil, tariquidar) as well as the kinase inhibitor bosutinib. ABCB1 internalization and MARCKS translocation was analyzed via confocal microscopy exploiting the endocytosis inhibitors chlorpromazine and dynasore. Abundance of PI(4,5)P 2 was monitored by intramolecular fluorescence resonance energy transfer (FRET). Reproductive cell survival was studied via colorimetric WST-1 and clonogenic assays in combination with exposure to the chemotherapeutics doxorubicin and 5-fuorouracil (5-FU). Results We found increased ABCB1 expression in MARCKS negative CRC patient tumor samples and established CRC cell lines. Mechanistically, the reconstitution of MARCKS function via recombinant expression or the pharmacological inhibition of MARCKS phosphorylation led to a substantial decrease in ABCB1 activity. In CRC cells, bosutinib treatment resulted in a MARCKS translocation from the cytosol to the plasma membrane, while simultaneously, ABCB1 was relocated to intracellular compartments. Inhibition of MARCKS phosphorylation via bosutinib rendered cells more sensitive to the chemotherapeutics doxorubicin and 5-FU. Conclusions Cells devoid of MARCKS function showed incomplete ABCB1 internalization, leading to higher ABCB1 activity enhancing chemoresistance. Vice versa our data suggest the prevention of MARCKS inhibition by reversing hyperphosphorylation or genomic restoration after deletion as two promising approaches to overcome tumor cell resistance towards chemotherapeutic ABCB1 substrates.

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Section: Role Of Marcks Phosphorylation For Regulation Of Abcb1 Functionsupporting

confidence: 64%

Section: Fret Imagingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Restoration of MARCK enhances chemosensitivity in cancer

Wenzel

Büch

Urban

et al. 2020

J Cancer Res Clin Oncol

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“…MARCKS increases cell motility through the protein kinase B pathway in fibroblasts21 and glial cells 22. Motility is also potentiated in macrophages,23 neutrophils,24 skeletal myoblasts,25 and endothelial cells26 through direct binding of MARCKS to actin. However, the mechanism through which MARCKS regulates VSMC motility is as yet unknown.…”

Section: Introductionmentioning

confidence: 99%

Myristoylated Alanine‐Rich Protein Kinase Substrate (MARCKS) Regulates Small GTPase Rac1 and Cdc42 Activity and Is a Critical Mediator of Vascular Smooth Muscle Cell Migration in Intimal Hyperplasia Formation

Makkar

Strickland

et al. 2015

JAHA

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BackgroundTranscription of the myristoylated alanine‐rich C kinase substrate (MARCKS) is upregulated in animal models of intimal hyperplasia. MARCKS knockdown inhibits vascular smooth muscle cell (VSMC) migration in vitro; however, the mechanism is as yet unknown. We sought to elucidate the mechanism of MARCKS‐mediated motility and determine whether MARCKS knockdown reduces intimal hyperplasia formation in vivo.Methods and Results MARCKS knockdown blocked platelet‐derived growth factor (PDGF)‐induced translocation of cortactin to the cell cortex, impaired both lamellipodia and filopodia formation, and attenuated motility of human coronary artery smooth muscle cells (CASMCs). Activation of the small GTPases, Rac1 and Cdc42, was prevented by MARCKS knockdown. Phosphorylation of MARCKS resulted in a transient shift of MARCKS from the plasma membrane to the cytosol. MARCKS knockdown significantly decreased membrane‐associated phosphatidylinositol 4,5‐bisphosphate (PIP 2) levels. Cotransfection with an intact, unphosphorylated MARCKS, which has a high binding affinity for PIP 2, restored membrane‐associated PIP 2 levels and was indispensable for activation of Rac1 and Cdc42 and, ultimately, VSMC migration. Overexpression of MARCKS in differentiated VSMCs increased membrane PIP 2 abundance, Rac1 and Cdc42 activity, and cell motility. MARCKS protein was upregulated early in the development of intimal hyperplasia in the murine carotid ligation model. Decreased MARKCS expression, but not total knockdown, attenuated intimal hyperplasia formation.Conclusions MARCKS upregulation increases VSMC motility by activation of Rac1 and Cdc42. These effects are mediated by MARCKS sequestering PIP 2 at the plasma membrane. This study delineates a novel mechanism for MARCKS‐mediated VSMC migration and supports the rational for MARCKS knockdown to prevent intimal hyperplasia.

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“…MeHg is known to induce reactive oxygen species (ROS) production, including hydrogen peroxide (H 2 O 2 ). Since the distinct role of MARCKS accompanying its phosphorylation in H 2 O 2 -mediated signaling pathway in bovine aortic endothelial cells has been reported [16, 18], MARCKS is possibly phosphorylated through mechanisms associated with MeHg-induced H 2 O 2 production in EA.hy926 cells. Although we previously reported that, in neuroblastoma cells, the MARCKS phosphorylation by MeHg exposure was mediated by protein kinase C activation and occurred in a Ca 2+ -dependent manner, the phosphorylation mechanisms in EA.hy926 cells are still not clear and remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

MARCKS is involved in methylmercury-induced decrease in cell viability and nitric oxide production in EA.hy926 cells

Dao

Islam

Sudo

et al. 2016

The Journal of Veterinary Medical Science

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Methylmercury (MeHg) is a persistent environmental contaminant that has been reported worldwide. MeHg exposure has been reported to lead to increased risk of cardiovascular diseases; however, the mechanisms underlying the toxic effects of MeHg on the cardiovascular system have not been well elucidated. We have previously reported that mice exposed to MeHg had increased blood pressure along with impaired endothelium-dependent vasodilation. In this study, we investigated the toxic effects of MeHg on a human endothelial cell line, EA.hy926. In addition, we have tried to elucidate the role of myristoylated alanine-rich C kinase substrate (MARCKS) in the MeHg toxicity mechanism in EA.hy926 cells. Cells exposed to MeHg (0.1–10 µM) for 24 hr showed decreased cell viability in a dose-dependent manner. Treatment with submaximal concentrations of MeHg decreased cell migration in the wound healing assay, tube formation on Matrigel and spontaneous nitric oxide (NO) production of EA.hy926 cells. MeHg exposure also elicited a decrease in MARCKS expression and an increase in MARCKS phosphorylation. MARCKS knockdown or MARCKS overexpression in EA.hy926 cells altered not only cell functions, such as migration, tube formation and NO production, but also MeHg-induced decrease in cell viability and NO production. These results suggest the broad role played by MARCKS in endothelial cell functions and the involvement of MARCKS in MeHg-induced toxicity.

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Angiotensin-II and MARCKS

Cited by 26 publications

References 51 publications

Restoration of MARCK enhances chemosensitivity in cancer

Restoration of MARCK enhances chemosensitivity in cancer

Myristoylated Alanine‐Rich Protein Kinase Substrate (MARCKS) Regulates Small GTPase Rac1 and Cdc42 Activity and Is a Critical Mediator of Vascular Smooth Muscle Cell Migration in Intimal Hyperplasia Formation

MARCKS is involved in methylmercury-induced decrease in cell viability and nitric oxide production in EA.hy926 cells

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