Stress-Induced Phosphorylation of Nuclear YB-1 Depends on Nuclear Trafficking of p90 Ribosomal S6 Kinase

Tiwari, Aadhya; Rebholz, Simone; Maier, Eva; Harati, Mozhgan Dehghan; Zips, Daniel; Sers, Christine; Rodemann, H. Peter; Toulany, Mahmoud

doi:10.3390/ijms19082441

Cited by 22 publications

(13 citation statements)

References 37 publications

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“…Inhibiting YB-1 phosphorylation on serine 102 with a mutation to alanine (S102A) prevented cell proliferation [ 48 , 49 ] and transactivation of various genes including EGFR [ 50 ] and PIK3CA [ 51 ] and NOTCH4 [ 52 ]. Protein Kinase B (AKT) [ 48 ], p90 S6 Ribosomal Kinase (RSK) [ 53 ] and Extracellular Signal Regulated Kinase (ERK) [ 49 , 54 ] have all been implicated in YB-1 S102 phosphorylation, and inhibiting RSK suppressed the ability of YB-1 to promote proliferation [ 53 , 55 ]. Inhibition of RSK/YB-1 signalling has shown to improve sensitivity of prostate cancer cells treated with enzalutamide [ 56 ].…”

Section: Resultsmentioning

confidence: 99%

Critical Role for Cold Shock Protein YB-1 in Cytokinesis

Mehta

Algie

Al-Jabry

et al. 2020

Cancers

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High levels of the cold shock protein Y-box-binding protein-1, YB-1, are tightly correlated with increased cell proliferation and progression. However, the precise mechanism by which YB-1 regulates proliferation is unknown. Here, we found that YB-1 depletion in several cancer cell lines and in immortalized fibroblasts resulted in cytokinesis failure and consequent multinucleation. Rescue experiments indicated that YB-1 was required for completion of cytokinesis. Using confocal imaging we found that YB-1 was essential for orchestrating the spatio-temporal distribution of the microtubules, β-actin and the chromosome passenger complex (CPC) to define the cleavage plane. We show that phosphorylation at six serine residues was essential for cytokinesis, of which novel sites were identified using mass spectrometry. Using atomistic modelling we show how phosphorylation at multiple sites alters YB-1 conformation, allowing it to interact with protein partners. Our results establish phosphorylated YB-1 as a critical regulator of cytokinesis, defining precisely how YB-1 regulates cell division.

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Section: Resultsmentioning

confidence: 99%

Critical Role for Cold Shock Protein YB-1 in Cytokinesis

Mehta

Algie

Al-Jabry

et al. 2020

Cancers

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“…Previous studies found that the phosphorylation of YB1 at S102 by AKT and RSK allows it to shuttle into the nucleus, enhances its binding to the promoters of some genes, and stimulates gene transcription by an unknown mechanism ( 2 , 52 ). On the other hand, it was also reported that acute stimulation of YB-1 phosphorylation does not promote YB-1 nuclear translocation ( 25 ) and both phosphorylated and non-phosphorylated YB-1 can be detected in the nucleus ( 53 ). Contrary to the reports that phosphorylation of YB-1 promotes its binding to DNA, the study on mouse MSY3 (YB-3) showed that phosphorylation decreases its binding to DNA ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Structural basis of DNA binding to human YB-1 cold shock domain regulated by phosphorylation

Zhang

Fan

et al. 2020

Nucleic Acids Research

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Human Y-box binding protein 1 (YB-1) is a multifunctional protein and overexpressed in many types of cancer. It specifically recognizes DNA/RNA through a cold shock domain (CSD) and regulates nucleic acid metabolism. The C-terminal extension of CSD and the phosphorylation of S102 are indispensable for YB-1 function. Until now, the roles of the C-terminal extension and phosphorylation in gene transcription and translation are still largely unknown. Here, we solved the structure of human YB-1 CSD with a C-terminal extension sequence (CSDex). The structure reveals that the extension interacts with several residues in the conventional CSD and adopts a rigid structure instead of being disordered. Either deletion of this extension or phosphorylation of S102 destabilizes the protein and results in partial unfolding. Structural characterization of CSDex in complex with a ssDNA heptamer shows that all the seven nucleotides are involved in DNA–protein interactions and the C-terminal extension provides a unique DNA binding site. Our DNA-binding study indicates that CSDex can recognize more DNA sequences than previously thought and the phosphorylation reduces its binding to ssDNA dramatically. Our results suggest that gene transcription and translation can be regulated by changing the affinity of CSDex binding to DNA and RNA through phosphorylation, respectively.

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“…It has been reported that p90 ribosomal S6 kinase (RSK), which acts downstream of ERK activity, is the major kinase regulating YB-1 phosphorylation at S102 [ 14 , 15 ]. Recently, we reported that phosphorylated YB-1 does not translocate to the nucleus [ 16 ]. Instead, phosphorylation of nuclear YB-1 after various cellular stress, e.g., ligand stimulation, irradiation, and expression of KRAS(G12V) , is regulated by nuclear translocation of phospho-RSK [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we reported that phosphorylated YB-1 does not translocate to the nucleus [ 16 ]. Instead, phosphorylation of nuclear YB-1 after various cellular stress, e.g., ligand stimulation, irradiation, and expression of KRAS(G12V) , is regulated by nuclear translocation of phospho-RSK [ 16 ]. Therefore, targeting RSK could be an efficient approach for eliminating tumor-initiating cells via YB-1 inactivation in triple-negative breast cancer (TNBC) [ 15 ] lacking the expression of estrogen, progesterone, and HER2 receptors.…”

Section: Introductionmentioning

confidence: 99%

Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers

Tiwari

Iida

Kosnopfel

et al. 2020

Cancers

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The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in KRAS mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (PIK3CA). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in KRAS(G13D)-mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus PIK3CA(H1047R)/PTEN(E307K) mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in KRAS-mutated cells is mainly dependent on the MAPK/ERK pathway, while in PIK3CA/PTEN-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC.

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Stress-Induced Phosphorylation of Nuclear YB-1 Depends on Nuclear Trafficking of p90 Ribosomal S6 Kinase

Cited by 22 publications

References 37 publications

Critical Role for Cold Shock Protein YB-1 in Cytokinesis

Critical Role for Cold Shock Protein YB-1 in Cytokinesis

Structural basis of DNA binding to human YB-1 cold shock domain regulated by phosphorylation

Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers

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