Phosphorylation of p62 by cdk1 Controls the Timely Transit of Cells through Mitosis and Tumor Cell Proliferation

Linares, Juan F.; Amanchy, Ramars; Diaz-Meco, Marı́a T.; Moscat, Jorge

doi:10.1128/mcb.01405-10

Cited by 9 publications

(14 citation statements)

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“…It has been shown that the Ser403 site on p62 is phosphorylated by casein kinase 2 (CK2) and Tank‐binding protein kinase 1 (TBK1) , while Thr269 and Ser272 sites are phosphorylated by cyclin‐dependent kinase 1 (CDK1) . We tested if ULK1 could induce p62 phosphorylation at these known sites.…”

Section: Resultsmentioning

confidence: 99%

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Sestrin2 promotes Unc‐51‐like kinase 1 mediated phosphorylation of p62/sequestosome‐1

Semple

Park

et al. 2014

The FEBS Journal

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Autophagy is a homeostatic process that is important for degrading protein aggregates, nutrient deposits, dysfunctional organelles and several signaling molecules. p62/sequestosome-1 is a protein that binds to several autophagy substrates, such as ubiquitinated proteins, damaged mitochondria and signaling molecules such as an Nrf2 inhibitor Keap1, promoting their autophagic degradation. Sestrin2, a stress-inducible protein, has been recently shown to bind to p62 and promote autophagic degradation of such p62 targets. Because Sestrin2 is a metabolic regulator that suppresses diverse age- and obesity-associated pathologies, the autophagy-controlling function of Sestrin2 may be important for its other physiological functions. However, the molecular mechanism of how Sestrin2 can promote clearance of p62-associated proteins has been unclear. Here we show that Sestrin2 physically associates with ULK1 and p62 to form a complex, in which both Sestrin2 and p62 become phosphorylated by ULK1 at multiple sites. Ser403 of p62, whose phosphorylation is known to promote autophagic degradation of p62 and its targets, is among the sites phosphorylated by ULK1. ULK1-mediated p62 phosphorylation was facilitated by Sestrin2 in cells as well as in vitro kinase assays. Consistent with this finding, oligomycin-induced energy deprivation, which strongly activates ULK1, provoked a robust Ser403 phosphorylation of p62 in wild-type (WT) mouse embryonic fibroblasts (MEF). However, in ULK1/2- and Sestrin2-deficient MEF, oligomycin-induced p62 phosphorylation was dramatically attenuated, suggesting that endogenous Sestrin2-ULK1/2 mainly mediates p62 phosphorylation in response to energetic stress. Taken together, this study identifies ULK1 as a new p62 Ser403 kinase and establishes Sestrin2 as a promoter of ULK1-mediated p62 phosphorylation.

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Section: Resultsmentioning

confidence: 99%

“…p62 is a signaling adaptor protein that has many cellular functions . Recent reports suggest that phosphorylation of p62 can alter its function in regulating autophagy and cell cycle . Specifically, phosphorylation of p62 at the Ser403 site is important for degradation of p62 and its target molecules .…”

Section: Discussionmentioning

confidence: 99%

Sestrin2 promotes Unc‐51‐like kinase 1 mediated phosphorylation of p62/sequestosome‐1

Semple

Park

et al. 2014

The FEBS Journal

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“…Of note, Chfr methylation correlates with the progression of HCC and is proposed to play a role in the pathogenesis of this cancer . Grb14 also forms in the liver a constitutive complex with the adapter p62/sqstm1, which controls the timely transit of cells through mitosis and tumor cell proliferation . Cell cycle progression could then be altered by the release of p62 consecutive with Grb14 silencing.…”

Section: Discussionmentioning

confidence: 99%

Growth factor receptor binding protein 14 inhibition triggers insulin‐induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma

et al. 2017

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“…In eukaryotic cells, autophagy is an intracellular metabolic system and degrades intracellular materials to maintain cell homeostasis . Autophagy can be detected through measuring the expression of LC3‐II and Beclin 1 by Western blotting assay . Our results showed that the expression of LC3‐II and Beclin 1 was increased significantly in Saos‐2 cells treated by WIN.…”

Section: Discussionmentioning

confidence: 75%

Inhibition of autophagy and enhancement of endoplasmic reticulum stress increase sensitivity of osteosarcoma Saos‐2 cells to cannabinoid receptor agonist WIN55,212‐2

Zhang

Gao

et al. 2016

Cell Biochemistry & Function

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WIN55,212-2, a cannabinoid receptor agonist, can activate cannabinoid receptors, which has proven anti-tumour effects in several tumour types. Studies showed that WIN can inhibit tumour cell proliferation and induce apoptosis in diverse cancers. However, the role and mechanism of WIN in osteosarcoma are still unclear. In this study, we examined the effect of WIN55,212-2 on osteosarcoma cell line Saos-2 in terms of cell viability and apoptosis. Meanwhile, we further explored the role of endoplasmic reticulum stress and autophagy in apoptosis induced by WIN55,212-2. Our results showed that the cell proliferation of Saos-2 was inhibited by WIN55,212-2 in a dose-dependent and time-dependent manner. WIN55,212-2-induced Saos-2 apoptosis through mitochondrial apoptosis pathway. Meanwhile, WIN55,212-2 can induce endoplasmic reticulum stress and autophagy in Saos-2 cells. Inhibition of autophagy and enhancement of endoplasmic reticulum stress increased apoptosis induced by WIN55,212-2 in Saos-2 cells. These findings indicated that WIN55,212-2 in combination with autophagic inhibitor or endoplasmic reticulum stress activator may shed new light on osteosarcoma treatment. Copyright © 2016 John Wiley & Sons, Ltd.

show abstract

Phosphorylation of p62 by cdk1 Controls the Timely Transit of Cells through Mitosis and Tumor Cell Proliferation

Cited by 9 publications

References 0 publications

Sestrin2 promotes Unc‐51‐like kinase 1 mediated phosphorylation of p62/sequestosome‐1

Sestrin2 promotes Unc‐51‐like kinase 1 mediated phosphorylation of p62/sequestosome‐1

Growth factor receptor binding protein 14 inhibition triggers insulin‐induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma

Inhibition of autophagy and enhancement of endoplasmic reticulum stress increase sensitivity of osteosarcoma Saos‐2 cells to cannabinoid receptor agonist WIN55,212‐2

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