RanBPM: a potential therapeutic target for modulating diverse physiological disorders

Das, Soumyadip; Suresh, Bharathi; Kim, Hyongbum; Ramakrishna, Suresh

doi:10.1016/j.drudis.2017.08.005

Cited by 10 publications

(19 citation statements)

References 90 publications

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“…The functions and targets of the CTLH complex are still elusive, however several subunits of the complex, studied in isolation, have been implicated in various cellular processes and regulations [23]. RanBPM in particular has been implicated in the regulation of several signaling pathways involved in cancer development [22,23]. The basis for this study was our previous observation that RanBPM downregulation correlated with ERK phosphorylation and pathway activation [21].…”

Section: Discussionmentioning

confidence: 99%

“…However, the mechanism by which RanBPM downregulates c-Raf remains unknown. RanBPM has been previously been implicated in the regulation of several cancer pathways and has been suggested to have tumour suppressive functions [22,23]. While initially studied in isolation, it has now become evident that RanBPM is part of a large complex called the C-terminal to LisH (CTLH) complex that has E3 ligase activity [23,24].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of c-Raf Stability through the CTLH Complex

McTavish

Bérubé-Janzen

Wang

et al. 2019

IJMS

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c-Raf is a central component of the extracellular signal-regulated kinase (ERK) pathway which is implicated in the development of many cancer types. RanBPM (Ran-Binding Protein M) was previously shown to inhibit c-Raf expression, but how this is achieved remains unclear. RanBPM is part of a recently identified E3 ubiquitin ligase complex, the CTLH (C-terminal to LisH) complex. Here, we show that the CTLH complex regulates c-Raf expression through a control of its degradation. Several domains of RanBPM were found necessary to regulate c-Raf levels, but only the C-terminal CRA (CT11-RanBPM) domain showed direct interaction with c-Raf. c-Raf ubiquitination and degradation is promoted by the CTLH complex. Furthermore, A-Raf and B-Raf protein levels are also regulated by the CTLH complex, indicating a common regulation of Raf family members. Finally, depletion of CTLH subunits RMND5A (required for meiotic nuclear division 5A) and RanBPM resulted in enhanced proliferation and loss of RanBPM promoted tumour growth in a mouse model. This study uncovers a new mode of control of c-Raf expression through regulation of its degradation by the CTLH complex. These findings also uncover a novel target of the CTLH complex, and suggest that the CTLH complex has activities that suppress cell transformation and tumour formation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of c-Raf Stability through the CTLH Complex

McTavish

Bérubé-Janzen

Wang

et al. 2019

IJMS

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“…IPO9 has been implicated in the regulation of a number of signaling pathways to regulate several cellular processes such as apoptosis, cell adhesion, migration, and transcription as well as plays a critical role during development. In addition, IPO9 has been shown to regulate pathways implicated in cancer and Alzheimer's disease, implying that IPO9 has important functions in both normal and pathological development . Interestingly, IPO9 possesses pro‐tumorigenic and tumor suppressive functions.…”

Section: Discussionmentioning

confidence: 99%

“…IPO9 acts as a pro‐tumorigenic protein by interacting with androgen receptor, S100A7, and MET proteins, resulting in tumor progression. By contrast, it acts as a tumor suppressive protein by interacting with p73, Mgl‐1, and BLT2 proteins, resulting in tumor regression …”

Section: Discussionmentioning

confidence: 99%

Differential Proteomic Analysis between Small Cell Lung Carcinoma (SCLC) and Pulmonary Carcinoid Tumors Reveals Molecular Signatures for Malignancy in Lung Cancer

Fujii

Miyata

Takahashi

et al. 2018

Proteomics Clinical Apps

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“…They bear four known domains and based on the distinctive presence of a PRY/SPRY domain they should more appropriately be called Scorpins, forming a separate subgroup by themselves as initially suggested by Hosono et al [ 18 ]. For more information about the structure and the putative functions not related to the DDR of the different domains of Scorpins we recommend the reading of earlier reviews [ 7 , 8 , 10 , 19 , 20 ].…”

Section: Scorpinsmentioning

confidence: 99%

Scorpins in the DNA Damage Response

Palmieri

Tessari

Coppola

2018

IJMS

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The DNA Damage Response (DDR) is a complex signaling network that comes into play when cells experience genotoxic stress. Upon DNA damage, cellular signaling pathways are rewired to slow down cell cycle progression and allow recovery. However, when the damage is beyond repair, cells activate complex and still not fully understood mechanisms, leading to a complete proliferative arrest or cell death. Several conventional and novel anti-neoplastic treatments rely on causing DNA damage or on the inhibition of the DDR in cancer cells. However, the identification of molecular determinants directing cancer cells toward recovery or death upon DNA damage is still far from complete, and it is object of intense investigation. SPRY-containing RAN binding Proteins (Scorpins) RANBP9 and RANBP10 are evolutionarily conserved and ubiquitously expressed proteins whose biological functions are still debated. RANBP9 has been previously implicated in cell proliferation, survival, apoptosis and migration. Recent studies also showed that RANBP9 is involved in the Ataxia Telangiectasia Mutated (ATM) signaling upon DNA damage. Accordingly, cells lacking RANBP9 show increased sensitivity to genotoxic treatment. Although there is no published evidence, extensive protein similarities suggest that RANBP10 might have partially overlapping functions with RANBP9. Like RANBP9, RANBP10 bears sites putative target of PIK-kinases and high throughput studies found RANBP10 to be phosphorylated following genotoxic stress. Therefore, this second Scorpin might be another overlooked player of the DDR alone or in combination with RANBP9. This review focuses on the relatively unknown role played by RANBP9 and RANBP10 in responding to genotoxic stress.

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RanBPM: a potential therapeutic target for modulating diverse physiological disorders

Cited by 10 publications

References 90 publications

Regulation of c-Raf Stability through the CTLH Complex

Regulation of c-Raf Stability through the CTLH Complex

Differential Proteomic Analysis between Small Cell Lung Carcinoma (SCLC) and Pulmonary Carcinoid Tumors Reveals Molecular Signatures for Malignancy in Lung Cancer

Scorpins in the DNA Damage Response

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