Subunit composition and developmental regulation of hepatic protein phosphatase 2A (PP2A)

Yoo, Sunny J.-S.; Boylan, Joan M.; Brautigan, David L.; Gruppuso, Philip A.

doi:10.1016/j.abb.2007.02.019

Cited by 10 publications

(18 citation statements)

References 45 publications

(28 reference statements)

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“…Association between the core enzyme, comprising the catalytic C and the scaffold A subunits, and regulatory B subunits is regulated by methylation of PP2A-C (33,41,68,69). There is also a second subset of B subunits whose association with the core enzyme is independent of PP2A-C methylation (33).…”

Section: Discussionmentioning

confidence: 99%

Impaired Cardiac Contractility in Mice Lacking Both the AE3 Cl−/HCO
Prasad
¹
,
Bódi
²
,
Meyer
³

et al. 2008
Journal of Biological Chemistry
29
6
46
2
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To analyze the cardiac functions of AE3, we disrupted its gene (Slc4a3) in mice. Cl ؊ /HCO 3 ؊ exchange coupled with Na ؉ -dependent acid extrusion can mediate pH-neutral Na ؉ uptake, potentially affecting Ca 2؉ handling via effects on Na ؉ /Ca 2؉ exchange. AE3 null mice appeared normal, however, and AE3 ablation had no effect on ischemia-reperfusion injury in isolated hearts or cardiac performance in vivo. The NKCC1 Na؊ cotransporter also mediates Na ؉ uptake, and loss of NKCC1 alone does not impair contractility. To further stress the AE3-deficient myocardium, we combined the AE3 and NKCC1 knock-outs. Double knock-outs had impaired contraction and relaxation both in vivo and in isolated ventricular myocytes. Ca 2؉ transients revealed an apparent increase in Ca 2؉ clearance in double null cells. This was unlikely to result from increased Ca 2؉ sequestration, since the ratio of phosphorylated phospholamban to total phospholamban was sharply reduced in all three mutant hearts. Instead, Na ؉ /Ca 2؉ exchanger activity was found to be enhanced in double null cells. Systolic Ca 2؉ was unaltered, however, suggesting more direct effects on the contractile apparatus of double null myocytes. Expression of the catalytic subunit of protein phosphatase 1 was increased in all mutant hearts. There was also a dramatic reversal, between single null and double null hearts, in the carboxymethylation and localization to the myofibrillar fraction, of the catalytic subunit of protein phosphatase 2A, which corresponded to the loss of normal contractility in double null hearts. These data show that AE3 and NKCC1 affect Ca 2؉ handling, PLN regulation, and expression and localization of major cardiac phosphatases and that their combined loss impairs cardiac function. At least four electroneutral ClϪ /HCO 3 Ϫ exchangers, termed AE1, AE2, AE3 (Slc4a1-3), and PAT1 or CFEX (Slc26a6), are expressed in cardiac muscle (1-6). Despite their abundance in the heart, which exceeds that of most other tissues (1, 6, 7), and the wealth of information about their epithelial functions, the physiological roles of sarcolemmal Cl

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Section: Discussionmentioning

confidence: 99%

Impaired Cardiac Contractility in Mice Lacking Both the AE3 Cl−/HCO
Prasad
¹
,
Bódi
²
,
Meyer
³

et al. 2008
Journal of Biological Chemistry
29
6
46
2
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“…All animal studies complied with guidelines set by the Rhode Island Hospital Institutional Animal Care and Use Committee. Rat liver extracts were prepared as previously described [Yoo et al, 2007]. …”

Section: Methodsmentioning

confidence: 99%

The α4‐containing form of protein phosphatase 2A in liver and hepatic cells

Yoo

Jimenez

Sanders

et al. 2008

J of Cellular Biochemistry

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The Ser/Thr phosphatase PP2A is a set of multisubunit enzymes that regulate many cellular processes. In yeast, the PP2A regulatory subunit Tap42 forms part of the Target of Rapamycin (TOR) signaling pathway that links nutrient and energy availability to cell growth. The physiological intersection between the mammalian orthologs of Tap42 and TOR, α4 and mTOR, has not been fully characterized. We used two in vivo models of liver growth in the rat, late gestation fetal development and regeneration after partial hepatectomy, to explore the regulation of the α4-containing form of PP2A. The α4/PP2A catalytic subunit (α4/PP2A-C) complex was present in both fetal and adult liver extracts. There was a trend towards higher levels of α4 protein in fetal liver, but the complex was more abundant in adult liver. Fractionation of extracts by ion exchange chromatography and transient transfection of the AML12 mouse hepatic cell line indicated that α4 associates with PP2A-C but that these complexes have low catalytic activity with both peptide and protein substrates. α4 was able to associate with forms of PP2A-C that were both methylated and non-methylated at the carboxy-terminus. The mTOR inhibitor rapamycin did not block the formation of α4/PP2A-C in liver or hepatic cells, nor did it appear to modulate PP2A activity. Furthermore, sensitivity to the growth inhibitory effects of rapamycin among a panel of hepatic cell lines did not correlate with levels of α4 or α4/PP2A-C. Our results indicate that the yeast Tap42/TOR paradigm is not conserved in hepatic cells. KeywordsProtein phosphorylation; mTOR; rapamycin; regeneration; cell growth PP2A is a major Ser/Thr phosphatase that plays a significant role in the regulation of many cellular processes, including metabolism, transcription, translation, cell cycle progression, cell growth and apoptosis [Janssens and Goris, 2001;Mumby and Walter, 1993;Sontag, 2001;Zolnierowicz, 2000]. The activity of such a versatile enzyme must therefore be tightly controlled in vivo. Indeed, the catalytic subunit of PP2A (PP2A-C) is regulated at many levels. The C-terminus of PP2A-C is post-translationally modified by phosphorylation at Y307 and methyl esterification at L309. Phosphorylation results in inhibition of PP2A activity [Chen et al., 1992;Guo and Damuni, 1993] while methylation is thought to play an important function in regulatory subunit binding [Bryant et al., 1999;Tolstykh et al., 2000;Wu et al., 2000;Yu et al., 2001]. More specifically, PP2A-C methylation can influence the association of PP2A-C with specific regulatory subunits, thereby serving to determine the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript composition, subcellular localization and function of PP2A-C holoenzymes in a variety of cell types [Gentry et al., 2005;Longin et al., 2007;Nunbhakdi-Craig et al., 2007].The prototypical PP2A enzyme is a heterodimer that consists of the catalytic C subunit and scaffolding A subunit. The substrate specificity and subcellular localization of PP2A are...

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“…It is important to note, however, that Pp2A is a very general phosphatase and that Igbp1 may control multiple cellular processes in addition to phosphorylation of 4EBP and p70 S6K, 30 whereas, on the other hand, Igbp1 only modulates a part of all cellular Pp2a (70 regulatory subunits are known to date 61,62 ). Lack of Igbp1 results in very early embryonal lethality, 28 and knockdown of Igbp1 would not give any insight into its importance in control of mRNA translation.…”

Section: The Role Of Igbp1 In Erythropoiesismentioning

confidence: 99%

“…60 Functional Pp2a consists of a catalytic subunit (Pp2a C ), a structural subunit (Pp2a A ), and a variable regulatory subunit (Pp2a B ). 61,62 One of these regulatory subunits is Igbp1, also known as ␣4. The interaction of Pp2a with Igbp1 was shown to inhibit its activity toward 4EBP and p70S6K, 44,45 but Pp2a activity on other targets is enhanced.…”

Section: The Role Of Igbp1 In Erythropoiesismentioning

confidence: 99%

Igbp1 is part of a positive feedback loop in stem cell factor–dependent, selective mRNA translation initiation inhibiting erythroid differentiation

Grech

Blázquez-Domingo

Kolbus

et al. 2008

Blood

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Subunit composition and developmental regulation of hepatic protein phosphatase 2A (PP2A)

Cited by 10 publications

References 45 publications

Impaired Cardiac Contractility in Mice Lacking Both the AE3 Cl−/HCO
Prasad
¹
,
Bódi
²
,
Meyer
³

et al. 2008
Journal of Biological Chemistry
29
6
46
2
View full text Add to dashboard Cite

Impaired Cardiac Contractility in Mice Lacking Both the AE3 Cl−/HCO
Prasad
¹
,
Bódi
²
,
Meyer
³

et al. 2008
Journal of Biological Chemistry
29
6
46
2
View full text Add to dashboard Cite

The α4‐containing form of protein phosphatase 2A in liver and hepatic cells

Igbp1 is part of a positive feedback loop in stem cell factor–dependent, selective mRNA translation initiation inhibiting erythroid differentiation

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Subunit composition and developmental regulation of hepatic protein phosphatase 2A (PP2A)

Cited by 10 publications

References 45 publications

Impaired Cardiac Contractility in Mice Lacking Both the AE3 Cl−/HCOPrasad1, Bódi2, Meyer3 et al. 2008Journal of Biological Chemistry296462View full textAdd to dashboardCite

Impaired Cardiac Contractility in Mice Lacking Both the AE3 Cl−/HCOPrasad1, Bódi2, Meyer3 et al. 2008Journal of Biological Chemistry296462View full textAdd to dashboardCite

The α4‐containing form of protein phosphatase 2A in liver and hepatic cells

Igbp1 is part of a positive feedback loop in stem cell factor–dependent, selective mRNA translation initiation inhibiting erythroid differentiation

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Impaired Cardiac Contractility in Mice Lacking Both the AE3 Cl−/HCO
Prasad
¹
,
Bódi
²
,
Meyer
³

et al. 2008
Journal of Biological Chemistry
29
6
46
2
View full text Add to dashboard Cite

Impaired Cardiac Contractility in Mice Lacking Both the AE3 Cl−/HCO
Prasad
¹
,
Bódi
²
,
Meyer
³

et al. 2008
Journal of Biological Chemistry
29
6
46
2
View full text Add to dashboard Cite