Association of Brain Protein Phosphatase 1 with Cytoskeletal Targeting/Regulatory Subunits

Colbran, Roger J.; Bass, Martha A.; McNeill, R. Blair; Bollen, Mathieu; Zhao, Sumin; Wadzinski, B E; Strack, Stefan

doi:10.1046/j.1471-4159.1997.69030920.x

Cited by 52 publications

(30 citation statements)

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“…Prior studies showed that anti-neurabin immune complexes from rat brain contained PP1␥1 but excluded PP1␤ (23). Far Westerns of brain extracts using recombinant PP1 catalytic subunits as probes suggested that neurabins displayed a significant preference for PP1␥1 and PP1␣ over PP1␤ (24). Our studies highlighted a domain in both neurabins that displayed PP1 isoform selectivity similar to the native proteins.…”

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confidence: 52%

The Neuronal Actin-binding Proteins, Neurabin I and Neurabin II, Recruit Specific Isoforms of Protein Phosphatase-1 Catalytic Subunits

Terry-Lorenzo

Carmody²,

Voltz³

et al. 2002

Journal of Biological Chemistry

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Neurabins are protein phosphatase-1 (PP1) targeting subunits that are highly concentrated in dendritic spines and post-synaptic densities. Immunoprecipitation of neurabin I and neurabin II/spinophilin from rat brain extracts sedimented PP1␥1 and PP1␣ but not PP1␤. In vitro studies showed that recombinant peptides representing central regions of neurabins also preferentially bound PP1␥1 and PP1␣ from brain extracts and associated poorly with PP1␤. Analysis of PP1 binding to chimeric neurabins suggested that sequences flanking a conserved PP1-binding motif altered their selectivity for PP1␤ and their activity as regulators of PP1 in vitro. Assays using recombinant PP1 catalytic subunits and a chimera of PP1 and protein phosphatase-2A indicated that the C-terminal sequences unique to the PP1 isoforms contributed to their recognition by neurabins. Collectively, the results from several different in vitro assays established the rank order of PP1 isoform selection by neurabins to be PP1␥1 > PP1␣ > PP1␤. This PP1 isoform selectivity was confirmed by immunoprecipitation of neurabin I and II from brain extracts from wild type and mutant PP1␥ null mice. In the absence of PP1␥1, both neurabins showed enhanced association with PP1␣ but not PP1␤. These studies identified some of the structural determinants in PP1 and neurabins that together contribute to preferential targeting of PP1␥1 and PP1␣ to the mammalian synapse.Protein phosphatase-1 (PP1), 1 a major eukaryotic protein serine/threonine phosphatase, is encoded by multiple genes in both plants and animals. Disruption of PP1 genes in fungi (1), fruit flies (2), and mice (3) suggested that PP1 isoforms encoded by individual genes control distinct but overlapping physiological functions. Three mammalian isoforms, PP1␣, PP1␤, and PP1␥1, are expressed in all tissues (4) with PP1␥2, an alternately spliced product of the PP1␥ gene, present predominantly in testes (5, 6). Immunocytochemistry using isoform-specific antibodies suggested that expression of PP1 isoforms varied in different brain regions where they are also localized to different subcellular compartments (6, 7). For example, PP1␤ was the predominant isoform associated with microtubules in the neuronal cell body, whereas PP1␥1 and PP1␣ were preferentially concentrated in dendritic spines (6,8). Furthermore, by analyzing endogenous PP1 movement during the cell cycle, Andreassen et al. (9) showed that the distribution of PP1 isoforms in cells was highly dynamic. This placed new emphasis on understanding the mechanisms that target individual PP1 isoforms to cellular organelles.Isolation of PP1 bound to skeletal muscle glycogen (10) and myosin (11) established the paradigm that regulatory or targeting subunits bound to PP1 catalytic subunits dictate the subcellular localization, substrate recognition, and hormonal control of PP1. The search for PP1 regulators that control functions as diverse as protein synthesis, gene expression, cell division, and motility has thus far yielded more than 50 PP1-binding proteins (12). Wh...

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confidence: 52%

The Neuronal Actin-binding Proteins, Neurabin I and Neurabin II, Recruit Specific Isoforms of Protein Phosphatase-1 Catalytic Subunits

Terry-Lorenzo

Carmody²,

Voltz³

et al. 2002

Journal of Biological Chemistry

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“…Antibodies-The following primary antibodies were used for immunoblotting (dilutions indicated) and/or for immunoprecipitation: whole serum and affinity-purified sheep and rabbit anti-PP1␥ 1 and anti-PP1␤ (7,36,37); mouse anti-tyrosine hydroxylase (ImmunoStar, 1:1000); mouse anti-PP2Ac (BD Transduction Laboratories, 1:4000); rabbit antibody to spinophilin (8) purified using protein A-Sepharose (Upstate); and mouse anti-spinophilin (BD Transduction Laboratories, 1:1000). Secondary antibodies were from Promega (goat antimouse HRP, 1:2000; goat anti-rabbit HRP, 1:4000), AlphaQuest (rabbit anti-goat HRP, 1:4000), or Santa Cruz Biotechnology (goat anti-mouse HRP or donkey anti-sheep HRP preadsorbed with human and/or mouse IgG, 1:5000).…”

Section: Methodsmentioning

confidence: 99%

Association of Protein Phosphatase 1γ1 with Spinophilin Suppresses Phosphatase Activity in a Parkinson Disease Model

Brown

Baucum

Bass

et al. 2008

Journal of Biological Chemistry

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Sustained nigrostriatal dopamine depletion increases the serine/threonine phosphorylation of multiple striatal proteins that play a role in corticostriatal synaptic plasticity, including Thr 286 phosphorylation of calcium/calmodulin-dependent protein kinase II␣ (CaMKII␣). Mechanisms underlying these changes are unclear, but protein phosphatases play a critical role in the acute modulation of striatal protein phosphorylation. Here we show that dopamine depletion for periods ranging from 3 weeks to 10 months significantly reduces the total activity of protein phosphatase (PP) 1, but not of PP2A, in whole lysates of rat striatum, as measured using multiple substrates, including Thr 286 -autophosphorylated CaMKII␣. Striatal PP1 activity is partially inhibited by a fragment of the PP1-binding protein neurabin-I, Nb-(146 -493), because of the selective inhibition of the PP1␥ 1 isoform. The fraction of PP1 activity that is insensitive to Nb-(146 -493) was unaffected by dopamine depletion, demonstrating that dopamine depletion specifically reduces the activity of PP1 isoforms that are sensitive to Nb-(146 -493) (i.e. PP1␥ 1 ). However, total striatal levels of PP1␥ 1 or any other PP1 isoform were unaffected by dopamine depletion, and our previous studies showed that total levels of the PP1 regulatory/targeting proteins DARPP-32, spinophilin, and neurabin were also unchanged. Rather, co-immunoprecipitation experiments demonstrated that dopamine depletion increases the association of PP1␥ 1 with spinophilin in striatal extracts. In combination, these data demonstrate that striatal dopamine depletion inhibits a specific synaptic phosphatase by increasing PP1␥ 1 interaction with spinophilin, perhaps contributing to hyperphosphorylation of synaptic proteins and disruptions of synaptic plasticity and/or dendritic morphology.Calcium/calmodulin-dependent protein kinase II (CaMKII) 3 and protein phosphatase 1 (PP1) are critical for synaptic plasticity. Autophosphorylation of CaMKII at Thr 286 is required for normal long term potentiation and hippocampus-based learning and memory (reviewed in Ref. 1). PP1 selectively dephosphorylates CaMKII that is associated with postsynaptic densities, whereas soluble CaMKII is primarily dephosphorylated by PP2A (2, 3). CaMKII has been shown to inhibit some forms of PP2A (4), but inhibition of PP1 via cAMP-dependent pathways promotes autophosphorylation at Thr 286 and long term potentiation induction (5, 6). Spinophilin and neurabin are similar F-actin-binding proteins that selectively target the PP1␥ 1 isoform to dendritic spines, modulating spine morphology and synaptic plasticity (7-16). Thus, coordinated regulation of CaMKII and PP1 is critical for normal synaptic physiology.Loss of nigrostriatal dopamine inputs in Parkinson disease or in parkinsonian animal models results in morphological alterations in striatal medium spiny neurons (MSNs) (17-22), which constitute Ͼ90% of the total striatal neuron population, and impairment of multiple forms of corticostriatal synaptic plasticity (23-26)....

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“…VIIA1). Notably, the PP1 binding module of Neurabins discriminates between PP1 isoforms, in that it prefers the ␣-subtype isoforms PP1␥ 1 and PP1␣ over PP1␤ (87,236,360). Finally, the COOH-terminal third of Neurabins includes a putative coiled-coil module and that of vertebrate Neurabin-I and of invertebrate Neurabins also a sterile ␣-motif.…”

Section: A Neurabin-associated Pp1mentioning

confidence: 99%

Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button

Ceulemans

Bollen

2004

Physiological Reviews

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Ceulemans, Hugo, and Mathieu Bollen. Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button. Physiol Rev 84: 1–39, 2004; 10.1152/physrev.00013.2003.—The protein serine/threonine phosphatase protein phosphatase-1 (PP1) is a ubiquitous eukaryotic enzyme that regulates a variety of cellular processes through the dephosphorylation of dozens of substrates. This multifunctionality of PP1 relies on its association with a host of function-specific targetting and substrate-specifying proteins. In this review we discuss how PP1 affects the biochemistry and physiology of eukaryotic cells. The picture of PP1 that emerges from this analysis is that of a “green” enzyme that promotes the rational use of energy, the recycling of protein factors, and a reversal of the cell to a basal and/or energy-conserving state. Thus PP1 promotes a shift to the more energy-efficient fuels when nutrients are abundant and stimulates the storage of energy in the form of glycogen. PP1 also enables the relaxation of actomyosin fibers, the return to basal patterns of protein synthesis, and the recycling of transcription and splicing factors. In addition, PP1 plays a key role in the recovery from stress but promotes apoptosis when cells are damaged beyond repair. Furthermore, PP1 downregulates ion pumps and transporters in various tissues and ion channels that are involved in the excitation of neurons. Finally, PP1 promotes the exit from mitosis and maintains cells in the G1or G2phases of the cell cycle.

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Association of Brain Protein Phosphatase 1 with Cytoskeletal Targeting/Regulatory Subunits

Cited by 52 publications

References 25 publications

The Neuronal Actin-binding Proteins, Neurabin I and Neurabin II, Recruit Specific Isoforms of Protein Phosphatase-1 Catalytic Subunits

The Neuronal Actin-binding Proteins, Neurabin I and Neurabin II, Recruit Specific Isoforms of Protein Phosphatase-1 Catalytic Subunits

Association of Protein Phosphatase 1γ1 with Spinophilin Suppresses Phosphatase Activity in a Parkinson Disease Model

Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button

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