Protein Phosphatase 2A Is Regulated by Protein Kinase Cα (PKCα)-dependent Phosphorylation of Its Targeting Subunit B56α at Ser41

Kirchhefer, Uwe; Heinick, Alexander; König, Simone; Kristensen, Torsten Nygaard; Müller, Frank; Seidl, Matthias D.; Boknı́k, Peter

doi:10.1074/jbc.m113.507996

Cited by 44 publications

(47 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1), and with diminished levels of the PDK1 kinase, suggesting diminished dephosphorylation of AKT, rather than induction of activatory kinases. Our data on a central role of the AKT and PKCa pathways in Trop-2 signaling are supported by reports showing that PKCa phosphorylates PP2A at the regulatory subunit and inhibits its activity, consequently reducing the rate of AKT dephosphorylation/inhibition (38). The AKT signaling cascades converge on GSK3 (39), promoting cell-cycle progression and survival.…”

Section: Akt Is a Required Mediator Of Trop-2 Downstream Signalingsupporting

confidence: 70%

Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Guerra

Trerotola

Tripaldi

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Inhibition of AKT is a key target area for personalized cancer medicine. However, predictive markers of response to AKT inhibitors are lacking. Correspondingly, the AKT-dependent chain of command for tumor growth, which will mediate AKTdependent therapeutic responses, remains unclear.Experimental Design: Proteomic profiling was utilized to identify nodal hubs of the Trop-2 cancer growth-driving network. Kinase-specific inhibitors were used to dissect Trop-2-dependent from Trop-2-independent pathways. In vitro assays, in vivo preclinical models, and case series of primary human breast cancers were utilized to define the mechanisms of Trop-2-driven growth and the mode of action of Trop-2-predicted AKT inhibitors.Results: Trop-2 and AKT expression was shown to be tightly coordinated in human breast cancers, with virtual overlap with AKT activation profiles at T308 and S473, consistent with functional interaction in vivo. AKT allosteric inhibitors were shown to only block the growth of Trop-2-expressing tumor cells, both in vitro and in preclinical models, being ineffective on Trop-2-null cells. Consistently, AKTtargeted siRNA only impacted on Trop-2-expressing cells. Lentiviral downregulation of endogenous Trop-2 abolished tumor response to AKT blockade, indicating Trop-2 as a mandatory activator of AKT.Conclusions: Our findings indicate that the expression of Trop-2 is a stringent predictor of tumor response to AKT inhibitors. They also support the identification of target-activatory pathways, as efficient predictors of response in precision cancer therapy. Clin Cancer Res; 22(16); 4197-205. Ó2016 AACR.

show abstract

Section: Akt Is a Required Mediator Of Trop-2 Downstream Signalingsupporting

confidence: 70%

Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Guerra

Trerotola

Tripaldi

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…1B). To dissect the relative contribution of the activities of PP1 and PP2A, phosphatase activity was also assayed in the presence of 3 nM okadaic acid, inhibiting only PP2A activity (13). PP2A activity was increased by almost 2-fold in TG compared with WT, which is in contrast to the unchanged PP1 activity between both groups (Fig.…”

Section: Resultsmentioning

confidence: 75%

“…This effect seems to be limited to the long term expression of B56␣, whereas the short term expression of this regulatory subunit in either adenovirus-infected rat cardiomyocytes (15) or transfected HEK293 cells (13) did not alter PP2A C levels. Interestingly, cardiomyocyte-directed overexpression of the catalytic subunit was not followed by an increase in the protein expression of B56␣ and PP2A A , as well (7).…”

Section: Discussionmentioning

confidence: 98%

“…It has been demonstrated that B56␣ is a phosphoprotein like most of the B56 family members (12). We have recently shown that nonphosphorylated B56␣ inhibited purified PP2A CA activity (13). The potency of B56␣ for PP2A inhibition was markedly increased by a phosphorylation of B56␣ at Ser 41 by PKC.…”

mentioning

confidence: 95%

“…B56␣-overexpressing Mice-B56␣ cDNA was generated as recently described (13). The amplified cDNA fragment contained engineered SalI restriction enzyme sites at both ends.…”

Section: Materials-[␥-mentioning

confidence: 99%

See 2 more Smart Citations

Cardiac Function Is Regulated by B56α-mediated Targeting of Protein Phosphatase 2A (PP2A) to Contractile Relevant Substrates

Kirchhefer

Brekle

Eskandar

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: PP2A is a regulator of cardiac excitation-contraction coupling. Results: Cardiomyocyte-directed overexpression of B56␣, the main cardiac PP2A regulatory subunit, results in the dephosphorylation of myofilament proteins, increased Ca 2ϩ sensitivity, and higher contractility. Conclusion: This suggests an important role for B56␣ in regulating PP2A activity and thereby the contractile function. Significance: PP2A-B56␣ is a potential pharmacological target to improve cardiac performance in failing hearts.

show abstract

HEK293 cells exposed to microcystin‐LR show reduced protein phosphatase 2A activity and more stable cytoskeletal structure when overexpressing α4 protein

Huang

Wang

Xing

et al. 2016

Environmental Toxicology

View full text Add to dashboard Cite

Microcystin-LR (MC-LR) is one of the most toxic members of microcystins released by freshwater cyanobacterial. The major mechanism of MC-LR toxicity has been attributed to its inhibition of protein phosphatases 1 (PP1) and 2A (PP2A). In our prior research, α4 protein, a regulator of PP2A, was found not only crucial for PP2A regulation but also for the overall response of HEK 293 cells encountering MC-LR. To explore the role of α4 in MC-LR toxicity via PP2A regulation, here, HEK 293 cells overexpressing α4 protein were exposed to MC-LR and PP2A, cytoskeletal organization, and cytoskeleton-related proteins were investigated. The results showed that PP2A activity decreased and PP2A/C subunit expression and phosphorylation at Tyr307 increased significantly in the group exposed to high MC-LR. Vimentin IF became concentrated and formed perinuclear bundles. However, the assembly of actin filament and microtubules remained unchanged and the expression and phosphorylation of the cytoskeleton-related proteins HSP27 and VASP did not increase significantly. Some of these results differ from those of our previous study in which normal HEK293 cells were exposed to MC-LR. Our results indicate that elevated α4 expression confers some resistance to MC-LR-induced cytoskeletal change These new findings provide helpful insights into the mechanism of MC-LR toxicity and the role of α4 in regulating PP2A function. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 255-264, 2017.

show abstract

Protein Phosphatase 2A Is Regulated by Protein Kinase Cα (PKCα)-dependent Phosphorylation of Its Targeting Subunit B56α at Ser41

Cited by 44 publications

References 53 publications

Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Trop-2 Induces Tumor Growth Through AKT and Determines Sensitivity to AKT Inhibitors

Cardiac Function Is Regulated by B56α-mediated Targeting of Protein Phosphatase 2A (PP2A) to Contractile Relevant Substrates

HEK293 cells exposed to microcystin‐LR show reduced protein phosphatase 2A activity and more stable cytoskeletal structure when overexpressing α4 protein

Contact Info

Product

Resources

About