The MLK-related Kinase (MRK) Is a Novel RhoC Effector That Mediates Lysophosphatidic Acid (LPA)-stimulated Tumor Cell Invasion*

Korkina, Olga; Dong, Zhiwan; Marullo, Allison; Warshaw, Gregg; Symons, Marc; Ruggieri, Rosamaria

doi:10.1074/jbc.m112.414060

Cited by 23 publications

(15 citation statements)

References 70 publications

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“…Additional work will be necessary to identify the mechanisms by which the differential activation kinetics of RhoA and RhoC are orchestrated during cell motility. The identification of additional GEFs that discriminate between RhoA and RhoC, as well as the identification of RhoC-specific effectors like FMLN2 [41] and MLK-related kinase [42], will aid in elucidating these mechanisms.…”

Section: Resultsmentioning

confidence: 99%

A RhoC Biosensor Reveals Differences in the Activation Kinetics of RhoA and RhoC in Migrating Cells

et al. 2013

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RhoA and RhoC GTPases share 92% amino acid sequence identity, yet play different roles in regulating cell motility and morphology. To understand these differences, we developed and validated a biosensor of RhoC activation (RhoC FLARE). This was used together with a RhoA biosensor to compare the spatio-temporal dynamics of RhoA and RhoC activity during cell protrusion/retraction and macropinocytosis. Both GTPases were activated similarly at the cell edge, but in regions more distal from the edge RhoC showed higher activation during protrusion. The two isoforms differed markedly in the kinetics of activation. RhoC was activated concomitantly with RhoA at the cell edge, but distally, RhoC activation preceded RhoA activation, occurring before edge protrusion. During macropinocytosis, differences were observed during vesicle closure and in the area surrounding vesicle formation.

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Section: Resultsmentioning

confidence: 99%

A RhoC Biosensor Reveals Differences in the Activation Kinetics of RhoA and RhoC in Migrating Cells

et al. 2013

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“…3 and Table I) from the about 1100 protein spots we have aligned. Among of them, six proteins including eIF3g, eIF-2-alpha, EF-1-alpha-1, EF-1-gamma, EF-1-delta, and AspRS have been shown to be involved in protein synthesis (26 -30), two proteins including RPS3a and GRP-78 have been shown to be able to inhibit apoptosis through various mechanism (31,32), and two proteins including PSMD11 and TXNL1 are components of the proteasome that have been shown to play a key role in regulating proteasome activity (33,34), the other five proteins also play important role in pathways such as tumor invasion and migration(RhoC) (35) protein modification (LS) (36), cell proliferation (PCNA) (37), macromolecular complex assembly (TCP-1-alpha) (38), and pre-mRNAs processing (hnRNP H and hnRNP H3) (39,40), indicating that these vital processes of the cell, such as proteostasis, primary metabolism, cell cycle and death, are all under the control of PI3K in A431 cells through maintaining the expression level of these short-lived central proteome members.…”

Section: Time Course Analysis Of Differently Expressed Proteins Durinmentioning

confidence: 99%

Proteomic Profiling Identified Multiple Short-lived Members of the Central Proteome as the Direct Targets of the Addicted Oncogenes in Cancer Cells

Zhang

Luan

et al. 2014

Molecular & Cellular Proteomics

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Oncogene addiction is an unexplained phenomenon in the area of cancer targeted therapy. In this study, we have tested a hypothesis that rapid apoptotic response of cancer cells following acute inhibition of the addicted oncogenes is due to loss of multiple short‐lived proteins whose activity normally maintain cell survival by blocking caspase activation directly or indirectly. It was shown that rapid apoptotic response or acute apoptosis could be induced in both A431 and MiaPaCa‐2 cells, and quick down‐regulation of 17 proteins, which were all members of the central proteome of human cells, was found to be associated with the onset of acute apoptosis. Knockdown of PSMD11 could partially promote the occurrence of acute apoptosis in both MiaPaCa‐2 and PANC‐1 pancreatic cancer cells. These findings indicate that maintaining the stability of central proteome may be a primary mechanism for addicted oncogenes to maintain the survival of cancer cells through various signaling pathways, and quick loss of some of the short‐lived members of the central proteome may be the direct reason for the rapid apoptotic response or acute apoptosis following acute inhibition of the addicted oncogenes in cancer cells. These findings we have presented can help us better understand the phenomenon of oncogene‐addiction and may have important implications for the targeted therapy of cancer. Grant Funding Source: Supported by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry

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“…Cells were cultured in DMEM containing 10% FBS, 1 mmol/L glutamine and 1% penicillin/streptomycin. UMDI cells are a derivative of the osteosarcoma cell line U2-OS, described in Korkina and colleagues (19). In UMDI cells, expressing plasmid pC4-Fv1E-MRK, MRK can be activated by induced homodimerization with the drug AP20187 (Clontech).…”

Section: Cell Lines and Transfectionsmentioning

confidence: 99%

“…We assessed their ability to inhibit MRK kinase activity using a cell-based assay that we previously described (19). Briefly, we made use of the M28 osteosarcoma cell derivative (UMDI) that expresses a recombinant form of MRK, which can be activated by homodimerization with the drug AP20187.…”

Section: Design Of An Irreversible Inhibitor Of Mrkmentioning

confidence: 99%

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Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma

Markowitz

Powell

Tran

et al. 2016

Molecular Cancer Therapeutics

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Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient-derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patientderived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects.

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The MLK-related Kinase (MRK) Is a Novel RhoC Effector That Mediates Lysophosphatidic Acid (LPA)-stimulated Tumor Cell Invasion*

Cited by 23 publications

References 70 publications

A RhoC Biosensor Reveals Differences in the Activation Kinetics of RhoA and RhoC in Migrating Cells

A RhoC Biosensor Reveals Differences in the Activation Kinetics of RhoA and RhoC in Migrating Cells

Proteomic Profiling Identified Multiple Short-lived Members of the Central Proteome as the Direct Targets of the Addicted Oncogenes in Cancer Cells

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma

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