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Science 22 May 1998:
Vol. 280. no. 5367, pp. 1258 - 1261
DOI: 10.1126/science.280.5367.1258
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Reports

A Signaling Complex of Ca2+-Calmodulin-Dependent Protein Kinase IV and Protein Phosphatase 2A

Ryan S. Westphal, *dagger Kristin A. Anderson, * Anthony R. Means, Brian E. Wadzinski ddagger

Stimulation of T lymphocytes results in a rapid increase in intracellular calcium concentration ([Ca2+]i) that parallels the activation of Ca2+-calmodulin-dependent protein kinase IV (CaMKIV), a nuclear enzyme that can phosphorylate and activate the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB). However, inactivation of CaMKIV occurs despite the sustained increase in [Ca2+]i that is required for T cell activation. A stable and stoichiometric complex of CaMKIV with protein serine-threonine phosphatase 2A (PP2A) was identified in which PP2A dephosphorylates CaMKIV and functions as a negative regulator of CaMKIV signaling. In Jurkat T cells, inhibition of PP2A activity by small t antigen enhanced activation of CREB-mediated transcription by CaMKIV. These findings reveal an intracellular signaling mechanism whereby a protein serine-threonine kinase (CaMKIV) is regulated by a tightly associated protein serine-threonine phosphatase (PP2A).

R. S. Westphal and B. E. Wadzinski, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
K. A. Anderson and A. R. Means, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
*   These authors contributed equally to this report.

dagger    Present address: Howard Hughes Medical Institute, Vollum Institute, Oregon Health Sciences University L-474, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA.

ddagger    To whom correspondence should be addressed.

Cellular responses to external signals require coordinated control of protein kinases and phosphatases; multiple complexes containing both intracellular signaling enzymes are likely to be important for the regulation and specificity of signal transduction pathways. The targeting of protein kinases and phosphatases to specific subcellular compartments, through association with scaffold proteins such as A-kinase anchoring proteins, may contribute to the specificity of cellular signaling (1). However, the enzymes are retained by the anchoring protein in their inactive state (2), and potential regulatory interactions within these multiprotein complexes remain unknown. Preexisting complexes containing active protein kinases and phosphatases provide an alternative and conceptually attractive mechanism by which the appropriate phosphorylation state of intracellular substrates is maintained. The alpha  subunit of casein kinase II (CKII), but not the CKII holoenzyme (containing alpha  and beta  subunits), associates with the catalytic (C) subunit of PP2A (3). This association was proposed as a mechanism for growth suppression in which CKIIalpha -stimulated phosphorylation of the C subunit of PP2A would increase the activity of the phosphatase. However, PP2A exists in cells as a heterotrimeric holoenzyme rather than as a free catalytic subunit (4), and phosphorylation of the C subunit of PP2A on Ser-Thr residues in vivo has not been shown.

CaMKIV is important for T cell activation (5). Stimulation of the T cell receptor (TCR) causes increases in [Ca2+]i and activation of CaMKIV. Because CaMKIV phosphorylates the nuclear protein CREB on Ser133, it appears to contribute to increased transcription of immediate early genes containing CRE sequences. The immediate early genes are required for increased expression of the interleukin-2 (IL-2) gene (6). Activation of CaMKIV in T cells is transient, rising to 15 times the background amount by 1 min after TCR stimulation and returning to basal activity within 5 min (7-9). This decline in CaMKIV activity occurs despite a maintained [Ca2+]i in excess of that needed for activation of the enzyme. After binding of Ca2+-calmodulin, CaMKIV is phosphorylated on a single Thr residue in the activation loop by a Ca2+-calmodulin-dependent kinase kinase (CaMKK) (9, 10) and, once activated, CaMKIV activity becomes independent of Ca2+ and calmodulin (8, 9, 11, 12). Because phosphorylation of CaMKIV is required to generate autonomous activity, we reasoned that a protein phosphatase might inactivate CaMKIV even in the presence of increased [Ca2+]i.

Phosphorylated CaMKIV (8) [as well as CREB phosphorylated on Ser133 (13)] is an in vitro substrate for PP2A. To determine whether these enzymes exist as a complex in cells, we immunoprecipitated CaMKIV from Jurkat T cells and analyzed the immune complex by immunoblotting with an antibody specific for the C subunit of PP2A. As shown in Fig. 1A, PP2A coimmunoprecipitated with CaMKIV (7). Because both CaMKIV and PP2A proteins are abundant in the brain, we used this tissue to further test whether CaMKIV and PP2A exist as a multiprotein complex. Rat brain soluble extracts were incubated with a glutathione S-transferase-CaMKIV (GST-CaMKIV) fusion protein (9). Both the C and Balpha regulatory subunits of PP2A were isolated with wild-type GST-CaMKIV (Fig. 1B). Because the B subunit is variable among holoenzyme preparations of PP2A, these results suggested the presence of a CaMKIV-PP2A holoenzyme complex.

Fig. 1. Identification of a CaMKIV-PP2A complex. (A) Coimmunoprecipitation of PP2A with CaMKIV. Immunoprecipitations from Jurkat T cell extracts were performed as described (7) with a rabbit polyclonal antibody raised against the COOH-terminal 17 residues of human CaM KIV (Imm.) or preimmune serum (Preimm.). Immune complexes were subjected to immunoblot analysis with a monoclonal antibody to the C subunit of PP2A (15). (B) Isolation of PP2A with a GST-CaMKIV fusion protein (9). Rat brain soluble extracts were incubated with buffer or wild-type GST-CaMKIV fusion protein (10 µg) for 3 hours at 4°C and then purified with glutathione-Sepharose (17). The resin was extensively washed and bound proteins were eluted with 20 mM glutathione, resolved by SDS-PAGE, and subjected to immunoblot analysis with antibodies to the C and Balpha regulatory subunits of PP2A. (C) Binding to calmodulin-Sepharose. Fractions containing proteins of large molecular mass (250 to 700 kD) from gel filtration of rat brain soluble extracts were incubated with calmodulin-Sepharose in the presence (+Ca2+) or absence (-Ca2+) of 5 mM CaCl2 (36). Bound proteins were eluted with 15 mM EGTA, resolved by SDS-PAGE, and subjected to protein immunoblotting with antibodies to the indicated PP2A subunits. (D) Elution of CaMKIV and PP2A from a Superdex-200 gel filtration column after sequential fractionation of brain extracts on phenyl-Sepharose, calmodulin-Sepharose, and Mono Q columns (14). Presented is an immunoblot of fractions from the final gel filtration column showing CaMKIV and the C and Balpha subunits of PP2A. Although not shown, the A subunit of PP2A was also present. (E) Calmodulin overlay was performed on fraction 23 of the gel filtration column in the presence of 1 mM Ca2+ or 1 mM EGTA (15). [View Larger Version of this Image (50K GIF file)]

To independently assess the presence of a complex, we tested whether PP2A holoenzyme bound calmodulin-Sepharose (an affinity resin for CaMKIV). A small fraction (less than 10%) of PP2A holoenzyme (ABalpha C) from rat brain soluble extracts bound calmodulin-Sepharose in a Ca2+-dependent manner (Fig. 1C). We attempted to copurify CaMKIV and PP2A from rat brain soluble extract by sequential purification on phenyl-Sepharose, calmodulin-Sepharose, Mono Q, and Superdex-200 gel filtration columns (14). Immunoblot analysis of the gel filtration fractions demonstrated that CaMKIV remained associated with the PP2A holoenzyme (Fig. 1D). Calmodulin overlay of the peak gel filtration fraction revealed the presence of a single Ca2+-calmodulin-binding protein that comigrated with CaMKIV (Fig. 1E). The CaMKIV-PP2A complex had an apparent molecular mass of 232 kD (from gel filtration chromatography), and both its size and protein immunoblot analysis (15) indicated that the PP2A heterotrimer and kinase were present in a 1:1 ratio. Furthermore, immune complexes obtained from the peak gel filtration fraction with an antibody specific for CaMKIV contained CaMKIV and PP2A in a 1:1 stoichiometry (7, 16).

To determine whether the kinase domain of CaMKIV is sufficient to interact with PP2A, and to test whether kinase activity was necessary for this interaction, we analyzed a series of GST-CaMKIV deletion and point mutants for their ability to interact with PP2A (9, 17). Wild-type and several mutant GST-CaMKIV fusion proteins associated with PP2A, but GST alone (Fig. 2A) or glutathione-Sepharose beads did not (18). As evidenced by the interaction of the deletion mutant that contained the entire catalytic domain (residues 1 to 317), association with PP2A did not require the autoinhibitory or calmodulin-binding domains of CaMKIV (Fig. 2A). In contrast, an NH2-terminal deletion mutant of CaMKIV that contained amino acid residues 306 to 474 did not interact with PP2A. Catalytically inactive GST-CaMKIV mutants and a mutant GST-CaMKIV (T200A) not activated by CaMKK (9) associated with PP2A; this demonstrated that neither CaMKIV activity nor its phosphorylation by CaMKK is required for interaction with PP2A.

Fig. 2. Independence of association of CaMKIV and PP2A from enzyme activity. (A) Isolation of PP2A with wild-type and mutant GST-CaMKIV fusion proteins (9, 17). Rat brain soluble extracts were incubated with the indicated GST fusion proteins (10 µg) and analyzed as described in Fig. 1. Data shown are from a single experiment repeated two to six times with various wild-type and mutant GST-CaMKIV fusion proteins. (B) Isolation of CaMKIV with microcystin-Sepharose. Rat brain or Jurkat T cell soluble extracts were incubated with microcystin-Sepharose in the absence (-) or presence (+) of the PP2A inhibitor microcystin (19). Bound proteins were eluted with SDS-PAGE sample buffer and subjected to immunoblot analysis with antibodies to the C subunit of PP2A and to CaMKIV. The rat brain immunoblot (middle) was stained with Ponceau S (left) to compare proteins eluted from microcystin-Sepharose (15). The locations of the A, Balpha , and C subunits of PP2A are marked by arrows. Results are representative of three independent experiments. [View Larger Version of this Image (20K GIF file)]

To test whether PP2A catalytic activity was required for association with CaMKIV, we used microcystin-Sepharose to purify PP2A from extracts prepared from rat brain and Jurkat T cells (19). Both PP2A and CaMKIV were isolated from the extracts with the resin (Fig. 2B). Because microcystin is an inhibitor of PP2A that binds to the substrate binding site of the phosphatase catalytic subunit (20), PP2A activity appeared not to be required for association with CaMKIV. Association of CaMKIV and PP2A with microcystin-Sepharose was attenuated by pretreatment of the extracts with free microcystin. Hence, the purification of the proteins by the affinity resin occurred in a microcystin-dependent fashion and was not a result of nonspecific association with the beads.

Although association of CaMKIV with PP2A did not require activity of either enzyme, we tested the potential activity of CaMKIV and PP2A toward each other in vitro. The highly enriched complex of CaMKIV-PP2A was incubated in the presence or absence of Ca2+-calmodulin, CaMKK, and the PP2A inhibitor okadaic acid, and the proteins were separated by SDS-polyacrylamide gel electrophoresis (PAGE). The only phosphorylated protein detected by autoradiography appeared to be CaMKIV, as indicated by its size and increased phosphorylation after treatment with CaMKK (Fig. 3). Immunoblot analysis confirmed that the only okadaic acid-sensitive phosphatase present in the preparation was PP2A (18). Thus, the enhanced phosphorylation of CaMKIV observed in the presence of okadaic acid (Fig. 3) indicates that CaMKIV is a substrate for PP2A and suggests that PP2A may also regulate CaMKIV activity in vivo.

Fig. 3. Dephosphorylation of CaMKIV by PP2A. A CaMKIV-PP2A preparation (Fig. 1, gel filtration fraction 23) was incubated for 15 min at 30°C in the presence of 10 mM MgCl2, 100 µM ATP, and [gamma -32P]ATP (2000 dpm/pmol) and the indicated components (+); CaMKK (0.53 ng/µl) 3 mM CaCl2, 1 µm calmodulin, and 1 µm okadaic acid. EGTA (25 mM) was added, and the incubation was continued an additional 30 min. Reactions were stopped with sample buffer and subjected to SDS-PAGE and autoradiography. [View Larger Version of this Image (56K GIF file)]

To determine whether PP2A regulates CaMKIV activity in intact cells, we examined the effects of SV40 small t antigen, a specific inhibitor of PP2A activity (21-24), on CaMKIV-mediated activation of CREB-dependent transcription in Jurkat T cells. We used a Gal4-CREB construct together with a 5×(Gal4)-luciferase reporter plasmid because this assay specifically requires phosphorylation of Ser133 of the Gal4-CREB molecule. This chimeric protein binds DNA as a monomer and is therefore not influenced by endogenous CREB or other proteins that can heterodimerize with CREB. Previous studies have established that CaMKIV activates transcription by direct phosphorylation of Gal4-CREB on Ser133 (25) and that this assay requires phosphorylation of CaMKIV by CaMKK (9, 25, 26). Expression of small t antigen augmented CaMKIV-mediated Gal4-CREB activity that had been elicited by the Ca2+ ionophore ionomycin (Fig. 4) or by the CD3 antibody (16). This effect appeared to be specific for Ca2+-dependent, CaMKIV-mediated activation of Gal4-CREB, as expression of small t antigen had no effect on its own or on Gal4-CREB activity stimulated by constitutively active cAMP-dependent protein kinase, which also specifically and directly phosphorylates Gal4-CREB on Ser133 but in a Ca2+-independent manner (25, 26). These results indicate that the CaMKIV-PP2A complex regulates CaMKIV activity and plays a key role in controlling CRE-mediated gene transcription in T cells.

Fig. 4. Regulation of CREB activity in Jurkat T cells. (A) Enhancement of CaMKIV-mediated CREB activity by small t antigen, an inhibitor of PP2A activity. Jurkat cells were transiently cotransfected with 5×(Gal4)-luciferase reporter plasmid (5 µg) and Gal4-CREB expression plasmid (5 µg) together with expression plasmids for CaMKIV (3 µg), small t (1 µg), or constitutively active protein kinase A (PKA, 0.1 µg), as indicated (37). Eighteen hours after transfection, cells were stimulated for 5 hours with buffer (control) or calcium ionophore (1 µM ionomycin) and assayed for luciferase activity. A low concentration of PKA expression plasmid cDNA (0.1 µg) was used in these experiments to achieve a small amount of luciferase activity. Increasing the amount of PKA expression plasmid resulted in a large increase in luciferase activity that also was unaffected by expression of small t (16). Bars represent the relative induction over the value for control plasmid alone, normalized for amount of protein and efficiency of transfection. The values are means ± SE (n = 4). (B) A model for Ca2+-mediated phosphorylation of CREB in T lymphocytes. [View Larger Version of this Image (17K GIF file)]

In T cells, the Ca2+-calmodulin-dependent dephosphorylation of nuclear factor of activated T cells (NFATc) by calcineurin allows its translocation from the cytosol to the nucleus, where it participates in the induction of IL-2 gene transcription (27-29). Sustained increases in [Ca2+]i during T cell activation maintain NFATc in the nucleus long enough to induce IL-2 transcription; once [Ca2+]i returns to basal amounts, NFAT is rapidly redistributed out of the nucleus to the cytosol (30, 31). Our experiments show how another Ca2+-initiated regulatory event (CaMKIV-stimulated gene transcription) may be inhibited without a decrease in [Ca2+]i. The CaMKIV-PP2A complex would permit rapid dephosphorylation and inactivation of CaMKIV.

The complex of CaMKIV and PP2A exists in resting T cells and is not altered as a function of time after activation (16). How, then, would phosphorylation of CaMKIV and CREB happen at all? Several possible mechanisms may explain the inactivation of CaMKIV in the face of a sustained elevation of [Ca2+]i. First, it is plausible that PP2A is constitutively active toward CaMKIV but that CaMKK transiently outpaces the phosphatase (before becoming inactive itself) to ensure that CaMKIV remains active long enough to phosphorylate CREB. After phosphorylation, a coactivator, phospho-CREB binding protein (CBP), is recruited to the transcription apparatus and CBP binding occurs through the region of CREB that includes Ser133 (32). A second possibility is that PP2A could be inhibited by a Ca2+-independent posttranslational modification such as phosphorylation (33) or by an additional interacting protein (34). Finally, it seems possible that the state of phosphorylation of CaMKIV could, by itself, regulate PP2A activity. Once CaMKIV binds calmodulin and is phosphorylated on Thr200 by CaMKK, it undergoes autophosphorylation on a number of Ser residues in the extreme NH2-terminus (9, 11). The function of some of these modifications is unknown, but could be to regulate activity of PP2A either directly or by recruitment of another protein to the complex.

Regardless of the additional mechanisms involved, our results may reveal a way in which the duration of immediate early gene expression can be regulated independently of [Ca2+]i. Our findings that CaMKIV-PP2A complexes also occur in the brain suggest that similar regulatory mechanisms may contribute to synaptic plasticity and its role in the molecular basis for memory, where the phosphorylation state of CREB is regulated in a Ca2+-dependent manner by CaMKIV (35).

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  38. Supported by NIH grants GM51366 (B.E.W.), GM33976 and HD07503 (A.R.M.), and NRSA F32 AI09258 (K.A.A.); by grants from the Vanderbilt Diabetes Research and Training Center (DK20593), Cancer Center (CA68485), and Center for Molecular Neuroscience (MH19732); and by the Keck Foundation (Duke University). B.E.W. is the recipient of a Faculty Development Award from the Pharmaceutical Research and Manufacturers of America Foundation. We thank R. Colbran, J. Scott, L. Limbird, D. Lovinger, L. Kerr, and S. Shenolikar for critical discussions of the data and manuscript.
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   Abstract »    Full Text »    PDF »
Positive Regulation of Raf1-MEK1/2-ERK1/2 Signaling by Protein Serine/Threonine Phosphatase 2A Holoenzymes.
D. G. Adams, R. L. Coffee Jr., H. Zhang, S. Pelech, S. Strack, and B. E. Wadzinski (2005)
J. Biol. Chem. 280, 42644-42654
   Abstract »    Full Text »    PDF »
Positive Regulation of I{kappa}B Kinase Signaling by Protein Serine/Threonine Phosphatase 2A.
A. E. Kray, R. S. Carter, K. N. Pennington, R. J. Gomez, L. E. Sanders, J. M. Llanes, W. N. Khan, D. W. Ballard, and B. E. Wadzinski (2005)
J. Biol. Chem. 280, 35974-35982
   Abstract »    Full Text »    PDF »
The Autonomous Activity of Calcium/Calmodulin-dependent Protein Kinase IV Is Required for Its Role in Transcription.
F. A. Chow, K. A. Anderson, P. K. Noeldner, and A. R. Means (2005)
J. Biol. Chem. 280, 20530-20538
   Abstract »    Full Text »    PDF »
Nuclear Calpain Regulates Ca2+-dependent Signaling via Proteolysis of Nuclear Ca2+/Calmodulin-dependent Protein Kinase Type IV in Cultured Neurons.
B. Tremper-Wells and M. L. Vallano (2005)
J. Biol. Chem. 280, 2165-2175
   Abstract »    Full Text »    PDF »
Redox Regulation of the Calcium/Calmodulin-dependent Protein Kinases.
C. J. Howe, M. M. LaHair, J. A. McCubrey, and R. A. Franklin (2004)
J. Biol. Chem. 279, 44573-44581
   Abstract »    Full Text »    PDF »
15-Deoxy-{Delta}12,14-prostaglandin J2-mediated ERK Signaling Inhibits Gram-negative Bacteria-induced RelA Phosphorylation and Interleukin-6 Gene Expression in Intestinal Epithelial Cells through Modulation of Protein Phosphatase 2A Activity.
P. A. Ruiz, S. C. Kim, R. B. Sartor, and D. Haller (2004)
J. Biol. Chem. 279, 36103-36111
   Abstract »    Full Text »    PDF »
Regulation and Function of the Calcium/Calmodulin-dependent Protein Kinase IV/Protein Serine/Threonine Phosphatase 2A Signaling Complex.
K. A. Anderson, P. K. Noeldner, K. Reece, B. E. Wadzinski, and A. R. Means (2004)
J. Biol. Chem. 279, 31708-31716
   Abstract »    Full Text »    PDF »
Catalytic Activity Is Required for Calcium/Calmodulin-dependent Protein Kinase IV to Enter the Nucleus.
S. M. Lemrow, K. A. Anderson, J. D. Joseph, T. J. Ribar, P. K. Noeldner, and A. R. Means (2004)
J. Biol. Chem. 279, 11664-11671
   Abstract »    Full Text »    PDF »
Gene expression profiles in children undergoing cardiac surgery for right heart obstructive lesions.
I. E. Konstantinov, J. G. Coles, C. Boscarino, M. Takahashi, J. Goncalves, J. Ritter, and G. S. Van Arsdell (2004)
J. Thorac. Cardiovasc. Surg. 127, 746-754
   Abstract »    Full Text »    PDF »
Distinct roles for PP1 and PP2A in the Neurospora circadian clock.
Y. Yang, Q. He, P. Cheng, P. Wrage, O. Yarden, and Y. Liu (2004)
Genes & Dev. 18, 255-260
   Abstract »    Full Text »    PDF »
A role of the TATA box and the general co-activator hTAFII130/135 in promoter-specific trans-activation by simian virus 40 small t antigen.
M. Johannessen, P. A. Olsen, R. Sorensen, B. Johansen, O. M. Seternes, and U. Moens (2003)
J. Gen. Virol. 84, 1887-1897
   Abstract »    Full Text »    PDF »
A genetically encoded fluorescent reporter reveals oscillatory phosphorylation by protein kinase C.
J. D. Violin, J. Zhang, R. Y. Tsien, and A. C. Newton (2003)
J. Cell Biol. 161, 899-909
   Abstract »    Full Text »    PDF »
Identification and Functional Analysis of Two Ca2+-binding EF-hand Motifs in the B"/PR72 Subunit of Protein Phosphatase 2A.
V. Janssens, J. Jordens, I. Stevens, C. Van Hoof, E. Martens, H. De Smedt, Y. Engelborghs, E. Waelkens, and J. Goris (2003)
J. Biol. Chem. 278, 10697-10706
   Abstract »    Full Text »    PDF »
Human T-lymphotropic Virus Type I Tax Activates I-kappa B Kinase by Inhibiting I-kappa B Kinase-associated Serine/Threonine Protein Phosphatase 2A.
D.-X. Fu, Y.-L. Kuo, B.-Y. Liu, K.-T. Jeang, and C.-Z. Giam (2003)
J. Biol. Chem. 278, 1487-1493
   Abstract »    Full Text »    PDF »
A Phytochrome-Associated Protein Phosphatase 2A Modulates Light Signals in Flowering Time Control in Arabidopsis.
D.-H. Kim, J.-G. Kang, S.-S. Yang, K.-S. Chung, P.-S. Song, and C.-M. Park (2002)
PLANT CELL 14, 3043-3056
   Abstract »    Full Text »    PDF »
Antiadrenergic effects of adenosine A1 receptor-mediated protein phosphatase 2a activation in the heart.
Q. Liu and P. A. Hofmann (2002)
Am J Physiol Heart Circ Physiol 283, H1314-H1321
   Abstract »    Full Text »    PDF »
Participation of the Calcium/Calmodulin-dependent Kinases in Hydrogen Peroxide-induced Ikappa B Phosphorylation in Human T Lymphocytes.
C. J. Howe, M. M. LaHair, J. A. Maxwell, J. T. Lee, P. J. Robinson, O. Rodriguez-Mora, J. A. McCubrey, and R. A. Franklin (2002)
J. Biol. Chem. 277, 30469-30476
   Abstract »    Full Text »    PDF »
Cyclin G2 Associates with Protein Phosphatase 2A Catalytic and Regulatory B' Subunits in Active Complexes and Induces Nuclear Aberrations and a G1/S Phase Cell Cycle Arrest.
D. A. Bennin, A. S. A. Don, T. Brake, J. L. McKenzie, H. Rosenbaum, L. Ortiz, A. A. DePaoli-Roach, and M. C. Horne (2002)
J. Biol. Chem. 277, 27449-27467
   Abstract »    Full Text »    PDF »
Regulation of Retinoid X Receptor Responsive Element-Dependent Transcription in T Lymphocytes by Ser/Thr Phosphatases: Functional Divergence of Protein Kinase C (PKC){theta} and PKC{alpha} in Mediating Calcineurin-Induced Transactivation.
M. Ishaq, M. Fan, K. Wigmore, A. Gaddam, and V. Natarajan (2002)
J. Immunol. 169, 732-738
   Abstract »    Full Text »    PDF »
Metaplastic Protein Phosphatases.
E. Klann (2002)
Learn. Mem. 9, 153-155
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Protein Phosphatase 2A Forms a Molecular Complex with Shc and Regulates Shc Tyrosine Phosphorylation and Downstream Mitogenic Signaling.
S. Ugi, T. Imamura, W. Ricketts, and J. M. Olefsky (2002)
Mol. Cell. Biol. 22, 2375-2387
   Abstract »    Full Text »    PDF »
Sp1 Transcriptional Activity Is Up-regulated by Phosphatase 2A in Dividing T Lymphocytes.
I. Lacroix, C. Lipcey, J. Imbert, and B. Kahn-Perles (2002)
J. Biol. Chem. 277, 9598-9605
   Abstract »    Full Text »    PDF »
Integrin {alpha}2{beta}1 Promotes Activation of Protein Phosphatase 2A and Dephosphorylation of Akt and Glycogen Synthase Kinase 3{beta}.
J. Ivaska, L. Nissinen, N. Immonen, J. E. Eriksson, V.-M. Kahari, and J. Heino (2002)
Mol. Cell. Biol. 22, 1352-1359
   Abstract »    Full Text »    PDF »
Dephosphorylation of Ser-259 Regulates Raf-1 Membrane Association.
M. Kubicek, M. Pacher, D. Abraham, K. Podar, M. Eulitz, and M. Baccarini (2002)
J. Biol. Chem. 277, 7913-7919
   Abstract »    Full Text »    PDF »
Protein Phosphatase 2A Interacts with and Directly Dephosphorylates RelA.
J. Yang, G.-H. Fan, B. E. Wadzinski, H. Sakurai, and A. Richmond (2001)
J. Biol. Chem. 276, 47828-47833
   Abstract »    Full Text »    PDF »
An NMDA Receptor Signaling Complex with Protein Phosphatase 2A.
S. F. Chan and N. J. Sucher (2001)
J. Neurosci. 21, 7985-7992
   Abstract »    Full Text »    PDF »
Expression of Ca2+/Calmodulin-dependent Protein Kinase IV (CaMKIV) Messenger RNA during Murine Embryogenesis.
S. L. Wang, T. J. Ribar, and A. R. Means (2001)
Cell Growth Differ. 12, 351-361
   Abstract »    Full Text »    PDF »
The Serine/Threonine Phosphatase, PP2A: Endogenous Regulator of Inflammatory Cell Signaling.
T. P. Shanley, N. Vasi, A. Denenberg, and H. R. Wong (2001)
J. Immunol. 166, 966-972
   Abstract »    Full Text »    PDF »
Multiple Signals Required for Cyclic AMP-Responsive Element Binding Protein (CREB) Binding Protein Interaction Induced by CD3/CD28 Costimulation.
C.-T. Yu, H.-m. Shih, and M.-Z. Lai (2001)
J. Immunol. 166, 284-292
   Abstract »    Full Text »    PDF »
Female Fertility Is Reduced in Mice Lacking Ca2+/Calmodulin-Dependent Protein Kinase IV.
J. Y. Wu, I. J. Gonzalez-Robayna, J. S. Richards, and A. R. Means (2000)
Endocrinology 141, 4777-4783
   Abstract »    Full Text »    PDF »
Meeting Report: Targeting Protein Phosphatases-Medicines for the New Millenium.
S. Shenolikar and D. L. Brautigan (2000)
Science Signaling 2000 , pe1
   Abstract »    Full Text »    PDF »
Cocaine and Antidepressant-Sensitive Biogenic Amine Transporters Exist in Regulated Complexes with Protein Phosphatase 2A.
A. L. Bauman, S. Apparsundaram, S. Ramamoorthy, B. E. Wadzinski, R. A. Vaughan, and R. D. Blakely (2000)
J. Neurosci. 20, 7571-7578
   Abstract »    Full Text »    PDF »
Protein Ligands to Hur Modulate Its Interaction with Target Mrnas in Vivo.
C. M. Brennan, I.-E. Gallouzi, and J. A. Steitz (2000)
J. Cell Biol. 151, 1-14
   Abstract »    Full Text »    PDF »
The B56alpha Regulatory Subunit of Protein Phosphatase 2A Is a Target for Regulation by Double-Stranded RNA-Dependent Protein Kinase PKR.
Z. Xu and B. R. G. Williams (2000)
Mol. Cell. Biol. 20, 5285-5299
   Abstract »    Full Text »
Reversible Phosphorylation of the Signal Transduction Complex in Drosophila Photoreceptors.
M. Liu, L. L. Parker, B. E. Wadzinski, and B.-H. Shieh (2000)
J. Biol. Chem. 275, 12194-12199
   Abstract »    Full Text »    PDF »
Regulation of Calcium-sensitive Tyrosine Kinase Pyk2 by Angiotensin II in Endothelial Cells. ROLES OF Yes TYROSINE KINASE AND TYROSINE PHOSPHATASE SHP-2.
H. Tang, Z. J. Zhao, E. J. Landon, and T. Inagami (2000)
J. Biol. Chem. 275, 8389-8396
   Abstract »    Full Text »    PDF »
WD40 Repeat Proteins Striatin and S/G2 Nuclear Autoantigen Are Members of a Novel Family of Calmodulin-binding Proteins That Associate with Protein Phosphatase 2A.
C. S. Moreno, S. Park, K. Nelson, D. Ashby, F. Hubalek, W. S. Lane, and D. C. Pallas (2000)
J. Biol. Chem. 275, 5257-5263
   Abstract »    Full Text »    PDF »
Transient Translocation and Activation of Protein Phosphatase 2A during Mast Cell Secretion.
R. I. Ludowyke, J. Holst, L.-M. Mudge, and A. T. R. Sim (2000)
J. Biol. Chem. 275, 6144-6152
   Abstract »    Full Text »    PDF »
Regulatory Cascades Involving Calmodulin-Dependent Protein Kinases.
A. R. Means (2000)
Mol. Endocrinol. 14, 4-13
   Full Text »
Transcriptional Regulation of Endothelial Nitric-oxide Synthase by an Interaction between Casein Kinase 2 and Protein Phosphatase 2A.
K. Cieslik, C.-M. Lee, J.-L. Tang, and K. K. Wu (1999)
J. Biol. Chem. 274, 34669-34675
   Abstract »    Full Text »    PDF »
A PP2A regulatory subunit positively regulates Ras-mediated signaling during Caenorhabditis elegans vulval induction.
D. S. Sieburth, M. Sundaram, R. M. Howard, and M. Han (1999)
Genes & Dev. 13, 2562-2569
   Abstract »    Full Text »
The Arabidopsis Homolog of Yeast TAP42 and Mammalian alpha 4 Binds to the Catalytic Subunit of Protein Phosphatase 2A and Is Induced by Chilling.
D. M. Harris, T. L. Myrick, and S. J. Rundle (1999)
Plant Physiology 121, 609-618
   Abstract »    Full Text »
Regulation of NMDA Receptors by an Associated Phosphatase-Kinase Signaling Complex.
R. S. Westphal, S. J. Tavalin, J. W. Lin, N. M. Alto, I. D. Fraser, L. K. Langeberg, M. Sheng, and J. D. Scott (1999)
Science 285, 93-96
   Abstract »    Full Text »
From genes to channels: normal mechanisms.
D. M. Roden and S. Kupershmidt (1999)
Cardiovasc Res 42, 318-326
   Abstract »    Full Text »    PDF »
Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein.
R. T. Peterson, B. N. Desai, J. S. Hardwick, and S. L. Schreiber (1999)
PNAS 96, 4438-4442
   Abstract »    Full Text »    PDF »
Differential Effects of a Calcineurin Inhibitor on Glutamate-induced Phosphorylation of Ca2+/Calmodulin-dependent Protein Kinases in Cultured Rat Hippocampal Neurons.
J. Kasahara, K. Fukunaga, and E. Miyamoto (1999)
J. Biol. Chem. 274, 9061-9067
   Abstract »    Full Text »    PDF »
Purification and Identification of a Novel Subunit of Protein Serine/Threonine Phosphatase 4.
S. Kloeker and B. E. Wadzinski (1999)
J. Biol. Chem. 274, 5339-5347
   Abstract »    Full Text »    PDF »
Calcium-Dependent Activation of TNF Family Gene Expression by Ca2+/Calmodulin Kinase Type IV/Gr and Calcineurin.
F. M. Lobo, R. Zanjani, N. Ho, T. A. Chatila, and R. L. Fuleihan (1999)
J. Immunol. 162, 2057-2063
   Abstract »    Full Text »    PDF »
Identification of a Domain of Axin That Binds to the Serine/Threonine Protein Phosphatase 2A and a Self-binding Domain.
W. Hsu, L. Zeng, and F. Costantini (1999)
J. Biol. Chem. 274, 3439-3445
   Abstract »    Full Text »    PDF »
Identification of Kinase-Phosphatase Signaling Modules Composed of p70 S6 Kinase-Protein Phosphatase 2A (PP2A) and p21-activated Kinase-PP2A.
R. S. Westphal, R. L. Coffee Jr., A. Marotta, S. L. Pelech, and B. E. Wadzinski (1999)
J. Biol. Chem. 274, 687-692
   Abstract »    Full Text »    PDF »
Cooperative Inhibition of T-Cell Antigen Receptor Signaling by a Complex between a Kinase and a Phosphatase.
J.-F. Cloutier and A. Veillette (1999)
J. Exp. Med. 189, 111-121
   Abstract »    Full Text »    PDF »
Signaling from Polyomavirus Middle T and Small T Defines Different Roles for Protein Phosphatase 2A.
K. P. Mullane, M. Ratnofsky, X. Culleré, and B. Schaffhausen (1998)
Mol. Cell. Biol. 18, 7556-7564
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A Ca2+/Calmodulin-Dependent Protein Kinase Modulates Drosophila Photoreceptor K+ Currents: A Role in Shaping the Photoreceptor Potential.
A. Peretz, I. Abitbol, A. Sobko, C.-F. Wu, and B. Attali (1998)
J. Neurosci. 18, 9153-9162
   Abstract »    Full Text »    PDF »
Raf-1-associated Protein Phosphatase 2A as a Positive Regulator of Kinase Activation.
D. Abraham, K. Podar, M. Pacher, M. Kubicek, N. Welzel, B. A. Hemmings, S. M. Dilworth, H. Mischak, W. Kolch, and M. Baccarini (2000)
J. Biol. Chem. 275, 22300-22304
   Abstract »    Full Text »    PDF »
Protein Phosphatase 2A Is Associated with Class C L-type Calcium Channels (Cav1.2) and Antagonizes Channel Phosphorylation by cAMP-dependent Protein Kinase.
M. A. Davare, M. C. Horne, and J. W. Hell (2000)
J. Biol. Chem. 275, 39710-39717
   Abstract »    Full Text »    PDF »
Cystic Fibrosis Pathogens Activate Ca2+-dependent Mitogen-activated Protein Kinase Signaling Pathways in Airway Epithelial Cells.
A. J. Ratner, R. Bryan, A. Weber, S. Nguyen, D. Barnes, A. Pitt, S. Gelber, A. Cheung, and A. Prince (2001)
J. Biol. Chem. 276, 19267-19275
   Abstract »    Full Text »    PDF »
Activation of Calcium/Calmodulin-dependent Protein Kinase IV in Long Term Potentiation in the Rat Hippocampal CA1 Region.
J. Kasahara, K. Fukunaga, and E. Miyamoto (2001)
J. Biol. Chem. 276, 24044-24050
   Abstract »    Full Text »    PDF »
Oxidative Stress Induces Neuronal Death by Recruiting a Protease and Phosphatase-gated Mechanism.
V. See and J.-P. Loeffler (2001)
J. Biol. Chem. 276, 35049-35059
   Abstract »    Full Text »    PDF »
The Cardiac-specific Nuclear delta B Isoform of Ca2+/Calmodulin-dependent Protein Kinase II Induces Hypertrophy and Dilated Cardiomyopathy Associated with Increased Protein Phosphatase 2A Activity.
T. Zhang, E. N. Johnson, Y. Gu, M. R. Morissette, V. P. Sah, M. S. Gigena, D. D. Belke, W. H. Dillmann, T. B. Rogers, H. Schulman, et al. (2002)
J. Biol. Chem. 277, 1261-1267
   Abstract »    Full Text »    PDF »
Defining Ca2+/Calmodulin-dependent Protein Kinase Cascades in Transcriptional Regulation.
E. E. Corcoran and A. R. Means (2001)
J. Biol. Chem. 276, 2975-2978
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Cerebellar Defects in Ca2+/Calmodulin Kinase IV-Deficient Mice.
T. J. Ribar, R. M. Rodriguiz, L. Khiroug, W. C. Wetsel, G. J. Augustine, and A. R. Means (2000)
J. Neurosci. 20, RC107
   Abstract »    Full Text »    PDF »


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