Differential expression, localization and activity of MARCKS between mantle cell lymphoma and chronic lymphocytic leukemia

Vargova, Jarmila; Vargová, Karin; Dusilkova, Nina; Kulvait, Vojtech; Pospíšil, Vít; Zavadil, Jiří; Trněný, Marek; Klener, Pavel; Stopka, Tomáš

doi:10.1038/bcj.2016.80

Cited by 5 publications

(6 citation statements)

References 15 publications

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“…We detected a notable interaction with transportin-1a nuclear import protein that regulates nuclear-cytoplasmic transport through adapter proteins (67). Transportin-1 and MARCKS interactions are previously unreported, but are consistent with emerging data that MARCKS is selectively imported into the nucleus in specific cell types (68), and our findings that only the PP mutant was not enriched in the nucleus suggests ED phosphorylation may inhibit its translocation through the nuclear membrane. Interaction with casein kinase 2 (CK2) and its central location in MARCKS protein network suggest it may also directly regulate MARCKS at the ED or other phosphorylation domains.…”

Section: Discussionsupporting

confidence: 92%

Myristoylated alanine-rich C-kinase substrate effector domain phosphorylation regulates the growth and radiation sensitization of glioblastoma

et al. 2019

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Glioblastoma harbors frequent alterations in receptor tyrosine kinases, phosphatidylinositol-3 kinase (PI3K) and phosphatase and tensin homolog (PTEN) that dysregulate phospholipid signaling driven tumor proliferation and therapeutic resistance. Myristoylated alanine-rich C-kinase substrate (MARCKS) is a 32 kDa intrinsically unstructured protein containing a polybasic (+13) effector domain (ED), which regulates its electrostatic sequestration of phospholipid phosphatidylinositol ( 4 , 5 )-bisphosphate (PIP2), and its binding to phosphatidylserine, calcium/calmodulin, filamentous actin, while also serving as a nuclear localization sequence. MARCKS ED is phosphorylated by protein kinase C (PKC) and Rho-associated protein kinase (ROCK) kinases; however, the impact of MARCKS on glioblastoma growth and radiation sensitivity remains undetermined. In the present study, using a tetracycline-inducible system in PTEN-null U87 cells, we demonstrate that MARCKS overexpression suppresses growth and enhances radiation sensitivity in vivo . A new image cytometer, Xcyto10, was utilized to quantify differences in MARCKS ED phosphorylation on localization and its association with filamentous actin. The overexpression of the non-phosphorylatable ED mutant exerted growth-suppressive and radiation-sensitizing effects, while the pseudo-phosphorylated ED mutant exhibited an enhanced colony formation and clonogenic survival ability. The identification of MARCKS protein-protein interactions using co-immunoprecipitation coupled with tandem mass spectrometry revealed novel MARCKS-associated proteins, including importin-β and ku70. On the whole, the findings of this study suggest that the determination of the MARCKS ED phosphorylation status is essential to understanding the impact of MARCKS on cancer progression.

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Section: Discussionsupporting

confidence: 92%

Myristoylated alanine-rich C-kinase substrate effector domain phosphorylation regulates the growth and radiation sensitization of glioblastoma

et al. 2019

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“…(3) MARCKS has an important role in the MCL pathogenesis and can function as an MCL biomarker. [ 19 ] Mantle Cell Lymphoma Disease signature MARCKS is upregulated in the Blastoid Variant of Mantle Cell Lymphoma. [ 123 ] Mantle Cell Lymphoma Disease signature MARCKS is less expressed in Mantle Cell Lymphoma with low levels of the long cyclin D1 transcript as compared to other MCL with a higher expression of cyclin D1 variant.…”

Section: Marcks Impacts the Development And Progression Of Blood Cancersmentioning

confidence: 99%

“…Several reports have identified MARCKS as a positive regulator of the carcinogenesis process in multiple hematological malignancies. In patients with mantle cell lymphoma (MCL), specifically, the Ser159/163 phosphorylated form of MARCKS has been reported to be upregulated [ 19 ]. Similarly, Sven and colleagues also report an increase in the expression of MARCKS in the blastoid variant of MCL, a rare, aggressive form of non-Hodgkin’s lymphoma (NHL) [ 123 ].…”

Section: Marcks Impacts the Development And Progression Of Blood Cancersmentioning

confidence: 99%

“…Remarkably, decreased expression of long cyclin D1 4.4 kb transcript is commonly associated with high proliferation rates and poor survival in MCL [ 151 , 152 ]. Likewise, Vargova et al identified a nearly four-fold downregulated expression of MARCKS in CLL as compared to the normal control subjects [ 19 ]. Mechanistically, the authors observed that a greater expression of the oncogenic miR-155 in CLL caused a sequence-specific suppression of the expression of MARCKS thereby controlling its cellular levels.…”

Section: Marcks Impacts the Development And Progression Of Blood Cancersmentioning

confidence: 99%

“…Within blood cancers, although there are several studies that have identified a potent role of deregulated MARCKS with the overall process of carcinogenesis [ 14 – 18 ], yet our overall understanding of the regulatory roles of the gene and the associated protein remains at a nascent stage. Whereas some hematological malignancies have stressed the importance of the phosphorylated form of MARCKS in cancer development [ 14 , 18 , 19 ], others specify the involvement of the unphosphorylated protein in governing disease outcomes [ 15 ]. Additionally, while MARCKS exists as a valuable candidate for anti-cancer therapies, currently our grasp on the strategies available to target the gene or protein is still evolving.…”

Section: Introductionmentioning

confidence: 99%

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Pathophysiological roles of myristoylated alanine-rich C-kinase substrate (MARCKS) in hematological malignancies

et al. 2021

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The myristoylated alanine-rich C-kinase substrate (MARCKS) protein has been at the crossroads of multiple signaling pathways that govern several critical operations in normal and malignant cellular physiology. Functioning as a target of protein kinase C, MARCKS shuttles between the phosphorylated cytosolic form and the unphosphorylated plasma membrane-bound states whilst regulating several molecular partners including, but not limited to calmodulin, actin, phosphatidylinositol-4,5-bisphosphate, and phosphoinositide-3-kinase. As a result of these interactions, MARCKS directly or indirectly modulates a host of cellular functions, primarily including cytoskeletal reorganization, membrane trafficking, cell secretion, inflammatory response, cell migration, and mitosis. Recent evidence indicates that dysregulated expression of MARCKS is associated with the development and progression of hematological cancers. While it is understood that MARCKS impacts the overall carcinogenesis as well as plays a part in determining the disease outcome in blood cancers, we are still at an early stage of interpreting the pathophysiological roles of MARCKS in neoplastic disease. The situation is further complicated by contradictory reports regarding the role of phosphorylated versus an unphosphorylated form of MARCKS as an oncogene versus tumor suppressor in blood cancers. In this review, we will investigate the current body of knowledge and evolving concepts of the physical properties, molecular network, functional attributes, and the likely pathogenic roles of MARCKS in hematological malignancies. Key emphasis will also be laid upon understanding the novel mechanisms by which MARCKS determines the overall disease prognosis by playing a vital role in the induction of therapeutic resistance. Additionally, we will highlight the importance of MARCKS as a valuable therapeutic target in blood cancers and will discuss the potential of existing strategies available to tackle MARCKS-driven blood cancers.

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MARCKS affects cell motility and response to BTK inhibitors in CLL

Beckmann

Berg

Dickhut

et al. 2021

Blood

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BTK inhibitors are highly active drugs for the treatment of CLL. To understand the response to BTK inhibitors on a molecular level, we performed (phospho)proteomic analyses under ibrutinib treatment. We identified 3466 proteins and 9184 phosphopeptides (representing 2854 proteins) in CLL cells exhibiting a physiological ratio of phosphorylated serines, threonines and tyrosines (pS:pT:pY). Expression of 83 proteins differed between unmutated IGHV (UM)-CLL and mutated IGHV (M)-CLL. Strikingly, UM-CLL cells showed higher basal phosphorylation levels than M-CLL samples. Effects of ibrutinib on protein phosphorylation levels were stronger in UM-CLL, especially on phosphorylated tyrosines. The differentially regulated phosphopeptides and proteins clustered in pathways regulating cell migration, motility, cytoskeleton composition and survival. One protein, MARCKS, showed striking differences in expression and phosphorylation level in UM-CLL versus M-CLL. MARCKS sequesters PIP2, thereby affecting central signaling pathways and clustering of the B cell receptor. Genetically induced loss of MARCKSignificantly increased AKT signaling and the migratory capacity. CD40L stimulation increased expression of MARCKS. BCR stimulation induced phosphorylation of MARCKS, which was reduced by BTK inhibitiors. In line with our in vitro findings, low MARCKS expression is associated with significantly higher treatment-induced leukocytosis and more pronounced decrease of nodal disease in CLL patients treated with acalabrutinib.

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Differential expression, localization and activity of MARCKS between mantle cell lymphoma and chronic lymphocytic leukemia

Cited by 5 publications

References 15 publications

Myristoylated alanine-rich C-kinase substrate effector domain phosphorylation regulates the growth and radiation sensitization of glioblastoma

Myristoylated alanine-rich C-kinase substrate effector domain phosphorylation regulates the growth and radiation sensitization of glioblastoma

Pathophysiological roles of myristoylated alanine-rich C-kinase substrate (MARCKS) in hematological malignancies

MARCKS affects cell motility and response to BTK inhibitors in CLL

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