Phosphorylation and inactivation of protein phosphatase 1 by cyclin-dependent kinases.

Dohadwala, Mariam; Silva, E F da Cruz e; Hall, Frederick L.; Williams, Richard; Carbonaro-Hall, D. A.; Nairn, Angus C.; Greengard, Paul; Berndt, Norbert

doi:10.1073/pnas.91.14.6408

Cited by 247 publications

(256 citation statements)

References 47 publications

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“…The association of Fer with PP1a might enhance the CDK dependent phosphorylation of PP1a on Thr320. Alternatively, Fer could attenuate the auto-or trans-dephosphorylation of PP1a on Thr320 (Dohadwala et al, 1994). It should be noted that we did not detect tyrosine-phosphorylated PP1a in Fer-expressing cells (data not shown), suggesting that the regulatory effect of Fer on PP1a is kinase activity independent, and may result from the physical interaction between these two proteins.…”

Section: Fer Maintains G1-s Transition In Malignant Cellsmentioning

confidence: 80%

“…The balance between these two opposing regulatory mechanisms determines the phosphorylation and activation state of pRB (Berndt et al, 1997). Phosphorylation of Thr320 in PP1a suppresses the phosphatase activity of that enzyme and increased phosphorylation level of Thr320 is inversely correlated with the phosphatase activity of PP1a in vivo (Dohadwala et al, 1994;Kwon et al, 1997;Liu et al, 1999). Conversely, dephosphorylation of the Thr320 site induces the phosphatase activity of PP1a toward pRB -siRNA or with fersiRNA in the absence or presence of cycloheximide.…”

Section: Knockdown Of Fer Leads To the Hypophosphorylation Of Pp1amentioning

confidence: 99%

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Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

et al. 2006

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Fer is a nuclear and cytoplasmic intracellular tyrosine kinase. Herein we show that Fer is required for cell-cycle progression in malignant cells. Decreasing the level of Fer using the RNA interference (RNAi) approach impeded the proliferation of prostate and breast carcinoma cells and led to their arrest at the G0/G1 phase. At the molecular level, knockdown of Fer resulted in the activation of the retinoblastoma protein (pRB), and this was reflected by profound hypo-phosphorylation of pRB on both cyclindependent kinase CDK4 and CDK2 phosphorylation sites. Dephosphorylation of pRB was not seen upon the direct targeting of either CDK4 or CDK2 expression, and was only partially achieved by the simultaneous depletion of these two kinases. Amino-acid sequence analysis revealed two protein phosphatase 1 (PP1) binding motifs in the kinase domain of Fer and the association of Fer with the pRB phosphatase PP1a was verified using co-immunoprecipitation analysis. Downregulation of Fer potentiated the activation of PP1a and overexpression of Fer decreased the enzymatic activity of that phosphatase. Our findings portray Fer as a regulator of cell-cycle progression in malignant cells and as a potential target for cancer intervention.

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Section: Fer Maintains G1-s Transition In Malignant Cellsmentioning

confidence: 80%

Section: Knockdown Of Fer Leads To the Hypophosphorylation Of Pp1amentioning

confidence: 99%

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

et al. 2006

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“…Since molecular reagents to PNUTS/R 111 are now available, we are currently pursuing this avenue of investigation. Alternatively, changes in PP1 catalytic activity may be due to the alternation of its phosphorylation state by cyclin-CDK complexes shown to a ect PP1 activity (Dohadwala et al, 1994;Villa-Moruzzi, 1992). Hypoxia-induced decrease in cyclin-CDK activities, as presented above, may in this way directly alter PP1 activity.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced pRB hypophosphorylation results from downregulation of CDK and upregulation of PP1 activities

1998

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Exposure of CV-1P cells to hypoxic conditions results in reversible cell cycle arrest concomitant with accumulation of pRB in the hypophosphorylated, growth suppressive form. Similar to cell cycle arrest induced by serum starvation, we show here that hypoxia-induced arrest is accompanied by a decrease in pRB-directed CDK4 and CDK2 activities, lower cyclin D and E protein levels, and by an increase in p27 protein abundance. Immunoprecipitation studies reveal an increase in p27 association with cyclin E-CDK2 complexes. In contrast to cell cycle arrest induced by serum starvation, hypoxia increases PP1-mediated pRB dephosphorylation. These data reveal that synergy between decreased pRB-directed cyclin/CDK activity and increased pRB-directed phosphatase activity contribute towards inducing and maintaining pRB in its hypophosphorylated, growth suppressive state during hypoxia.

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“…Dephosphorylation of Rb is catalysed by a type-1 protein phosphatase (PP1), whose activity is inhibited by cyclin/Cdk complexes (Dohadwala et al, 1994;Kwon et al, 1997 …”

Section: The Retinoblastoma Proteinmentioning

confidence: 99%

A model for restriction point control of the mammalian cell cycle

Novák

Tyson

2004

Journal of Theoretical Biology

269

279

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Phosphorylation and inactivation of protein phosphatase 1 by cyclin-dependent kinases.

Abstract: Protein phohatase 1 and protein phospha-

Cited by 247 publications

References 47 publications

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

Hypoxia-induced pRB hypophosphorylation results from downregulation of CDK and upregulation of PP1 activities

A model for restriction point control of the mammalian cell cycle

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