Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells

Santio, Niina M.; Landor, Sebastian K.-J.; Vahtera, Laura; Ylä-Pelto, Jani; Paloniemi, Elina; Imanishi, Susumu Y.; Corthals, Garry L.; Varjosalo, Markku; Manoharan, Ganesh babu; Uri, Asko; Lendahl, Urban; Sahlgren, Cecilia; Koskinen, Päivi J.

doi:10.18632/oncotarget.9215

Cited by 54 publications

(86 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…28 Interestingly, phosphorylation of Notch-1 by Pim (proviral insertion in murine) kinases promoted oncogenic signaling in prostate cancer cells. 29 Recently, one study identified that inhibition of Notch pathway arrested PTEN-deficient advanced prostate cancer via enhancing p27-driven cellular senescence. 30 Studies investigated the function of Notch signaling pathway in prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

et al. 2017

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

et al. 2017

View full text Add to dashboard Cite

“…Moreover, NDRG1 expression in HepG2 cells leads to increased membrane-localized beta-catenin, which promotes a less migratory phenotype and greater cell-cell contact 45 . In light of these findings, and given the previously demonstrated ability of PIM1 to promote cell migration and invasion 58,59 , we investigated the effect of NDRG1 phosphorylation on the migration and invasion of prostate cancer cells. To examine migration, we exogenously expressed WT NDRG1 or NDRG1 S330A in PIM1 overexpressing LNCaP and VCaP cells (Suppl.…”

Section: Ndrg1 Ps330 Is Associated With Inhibition Of Prostate Cancermentioning

confidence: 99%

Identification of PIM1 substrates reveals a role for NDRG1 in prostate cancer cellular migration and invasion

Ledet

Ruff

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

PIM1 is an oncogenic serine/threonine kinase that promotes and maintains prostate tumorigenesis. To more fully understand the mechanism by which PIM1 promotes oncogenesis, we performed a chemical genetic screen to identify direct PIM1 substrates in prostate cancer cells. The PIM1 substrates we identified were involved in a variety of oncogenic processes, and included N-Myc Downstream-Regulated Gene 1 (NDRG1), which has reported roles in the suppression of cancer cell invasion and metastasis. NDRG1 is phosphorylated by PIM1 at serine 330 (pS330), and the level of NDRG1 pS330 is associated with high grade compared to low grade prostate tumors. While NDRG1 pS330 is largely cytoplasmic, total NDRG1 is both cytoplasmic and nuclear. Mechanistically, PIM1 phosphorylation of NDRG1 decreases its stability, reducing its interaction with AR, and thereby lowering expression of AR target genes.PIM1-dependent NDRG1 phosphorylation also reduces NDRG1's ability to suppress prostate cancer cell migration and invasion. Our study identifies a novel set of PIM1 substrates in prostate cancer cells using a direct, unbiased chemical genetic screen. It also provides key insights into the mechanisms by which PIM1-mediated phosphorylation of NDRG1 impairs its function, resulting in enhanced cell migration and invasion.

show abstract

“…Previous reports have proposed a number of potential kinases which may be involved in NICD phosphorylation and turnover, including CyclinC:CDK8 [36], CyclinC:CDKs [63], PKC [66], PIM [67] and GSK3b [35,37] kinases. The MRC-PPU Kinase Profiling Inhibitor Database (http://www.kinase-screen.mrc.ac.uk/kinaseinhibitors) (University of Dundee) indicates that, at the concentrations used in our assays, Roscovitine, in particular, is a potent inhibitor of CDK2, but a very weak inhibitor of CK1, GSK3b and more than 50 other kinases tested.…”

Section: Cyclin-dependent Kinase (Cdk) 1 and 2 Phosphorylate Nicd In mentioning

confidence: 99%

CDK 1 and CDK 2 regulate NICD 1 turnover and the periodicity of the segmentation clock

et al. 2019

View full text Add to dashboard Cite

All vertebrates share a segmented body axis. Segments form from the rostral end of the presomitic mesoderm (PSM) with a periodicity that is regulated by the segmentation clock. The segmentation clock is a molecular oscillator that exhibits dynamic clock gene expression across the PSM with a periodicity that matches somite formation. Notch signalling is crucial to this process. Altering Notch intracellular domain (NICD) stability affects both the clock period and somite size. However, the mechanism by which NICD stability is regulated in this context is unclear. We identified a highly conserved site crucial for NICD recognition by the SCF E3 ligase, which targets NICD for degradation. We demonstrate both CDK1 and CDK2 can phosphorylate NICD in the domain where this crucial residue lies and that NICD levels vary in a cell cycle‐dependent manner. Inhibiting CDK1 or CDK2 activity increases NICD levels both in vitro and in vivo, leading to a delay of clock gene oscillations and an increase in somite size.

show abstract

Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells

Cited by 54 publications

References 59 publications

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

Identification of PIM1 substrates reveals a role for NDRG1 in prostate cancer cellular migration and invasion

CDK 1 and CDK 2 regulate NICD 1 turnover and the periodicity of the segmentation clock

Contact Info

Product

Resources

About