The Akt-SRPK-SR Axis Constitutes a Major Pathway in Transducing EGF Signaling to Regulate Alternative Splicing in the Nucleus

Zhou, Zhihong; Qiu, Jinsong; Li, Wen; Zhou, Yu; Plocinik, Ryan M.; Li, Hairi; Hu, Qidong; Ghosh, Gourisanker; Adams, Joseph A.; Rosenfeld, Michael G.; Fu, Xiang‐Dong

doi:10.1016/j.molcel.2018.08.024

Cited by 11 publications

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“…To further compare the molecular changes elicited by cytoplasmic FUS mislocalization and FUS loss of function, we asked whether regulation of mRNA splicing was similarly affected in E18.5 brains of Fus ΔNLS/ΔNLS mice and Fus − / − mice. To characterize mRNA splicing, we exploited the RNA‐mediated oligonucleotide annealing, selection, and ligation with next‐generation sequencing (RASL‐seq) method (Li et al , ; Zhou et al , ). This approach allowed us to quantitatively profile 3,859 unique alternative splicing events that correspond to exon inclusion or skipping events conserved between mouse and human (Fig EV4).…”

Section: Resultsmentioning

confidence: 99%

Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss

et al. 2016

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FUS is an RNA‐binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS‐containing aggregates are often associated with concomitant loss of nuclear FUS. Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell‐specific CRE‐mediated expression of wild‐type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons.

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Section: Resultsmentioning

confidence: 99%

Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss

et al. 2016

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“…The phosphorylation state of splicing factors has been reported to affect almost all steps of AS (Misteli, ). In general, AKT can directly phosphorylate SR proteins (Bavelloni et al ., ; Shultz et al ., ) or indirectly act on splicing regulation by SRPKs, leading to the translocation of SRPKs into the nucleus and thereby modifying SR protein activities (Zhou et al ., ). Thus, BS008 decreasing the expression levels of SRPKs may cause AKT to fail to phosphorylate SR proteins through the AKT–SRPK–SR pathway.…”

Section: Discussionmentioning

confidence: 99%

Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxide

Lee

Chang

et al. 2019

Molecular Oncology

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Alternative splicing (AS) is a process that enables the generation of multiple protein isoforms with different biological properties from a single mRNA. Cancer cells often use the maneuverability conferred by AS to produce proteins that contribute to growth and survival. In our previous studies, we identified that amiloride modulates AS in cancer cells. However, the effective concentration of amiloride required to modulate AS is too high for use in cancer treatment. In this study, we used computational algorithms to screen potential amiloride derivatives for their ability to regulate AS in cancer cells. We found that 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxamide (BS008) can regulate AS of apoptotic gene transcripts, including HIPK3 , SMAC , and BCL‐X , at a lower concentration than amiloride. This splicing regulation involved various splicing factors, and it was accompanied by a change in the phosphorylation state of serine/arginine‐rich proteins (SR proteins). RNA sequencing was performed to reveal that AS of many other apoptotic gene transcripts, such as AATF , ATM , AIFM1 , NFKB1 , and API5 , was also modulated by BS008. In vivo experiments further indicated that treatment of tumor‐bearing mice with BS008 resulted in a marked decrease in tumor size. BS008 also had inhibitory effects in vitro , either alone or in a synergistic combination with the cytotoxic chemotherapeutic agents sorafenib and nilotinib. BS008 enabled sorafenib dose reduction without compromising antitumor activity. These findings suggest that BS008 may possess therapeutic potential for cancer treatment.

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“…The Akt kinase system is recognized to be involved in the mediation of cell proliferation, migration, and apoptosis in mammalian cells . Activated Akt has been found to induce SRPK1 phosphorylation in vitro, which could also be inhibited by the Akt‐specific suppressor MK2206 . Moreover, Zhou et al reported that activated Akt may lead to SRPK1 autophosphorylation, which causes SRPK1 to translocate into the nucleus and enhances the phosphorylation of downstream splicing.…”

Section: Discussionmentioning

confidence: 99%

“…Serine‐arginine protein‐specific kinases (SRPKs) are pivotal regulators in transducing growth signals from the cell surface to the nucleus in order to regulate mRNA splicing . The structure of SRPKs comprises a conserved kinase domain which is separated by a large, non‐conserved insert domain approximately 250 amino acids in size .…”

Section: Introductionmentioning

confidence: 99%

SRPK1 gene silencing promotes vascular smooth muscle cell proliferation and vascular remodeling via inhibition of the PI3K/Akt signaling pathway in a rat model of intracranial aneurysms

Wang

2018

CNS Neurosci Ther

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The Akt-SRPK-SR Axis Constitutes a Major Pathway in Transducing EGF Signaling to Regulate Alternative Splicing in the Nucleus

Cited by 11 publications

References 0 publications

Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss

Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss

Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5‐diamino‐6‐chloro‐N‐(N‐(2,6‐dichlorobenzoyl)carbamimidoyl)pyrazine‐2‐carboxide

SRPK1 gene silencing promotes vascular smooth muscle cell proliferation and vascular remodeling via inhibition of the PI3K/Akt signaling pathway in a rat model of intracranial aneurysms

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