Any feedback?
Please rate this page
(literature.php)
(0/150)

BRENDA support

Literature summary for 3.1.3.16 extracted from

  • Hoffman, A.; Taleski, G.; Sontag, E.
    The protein serine/threonine phosphatases PP2A, PP1 and calcineurin A triple threat in the regulation of the neuronal cytoskeleton (2017), Mol. Cell. Neurosci., 84, 119-131 .
    View publication on PubMed

Activating Compound

Activating Compound Comment Organism Structure
Calmodulin calcineurin is a calcium- and calmodulin-dependent enzyme Homo sapiens

Application

Application Comment Organism
drug development calcineurin is the principal target of the immunosuppressive drugs, cyclosporin A and FK506/Tacrolimus, the binding of which physically prevents the recruitment of macromolecular substrates to the active site Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
cyclosporin A calcineurin is the principal target of the immunosuppressive drugs, cyclosporin A and FK506/Tacrolimus, the binding of which physically prevents the recruitment of macromolecular substrates to the active site Homo sapiens
additional information calcineurin shows low sensitivity to inhibitory toxins such as okadaic acid and microcystin-LR, due to a divergent amino acid sequence in the beta12-beta33 loop of phosphatase PP1c Homo sapiens
okadaic acid PP2A activity is also regulated by many cellular regulators and natural inhibitors, such as okadaic acid. The commonly used inhibitor not only inhibits all PP2A isoforms, but also other Ser/Thr phosphatases, including PP1 and other PPP family members, at the concentrations needed to completely abrogate cellular PP2A activity; the commonly used inhibitor not only inhibit Ser/Thr phosphatases, including PP1 and other PPP family members, but also all PP2A isoforms Homo sapiens
tacrolimus calcineurin is the principal target of the immunosuppressive drugs, cyclosporin A and FK506/Tacrolimus, the binding of which physically prevents the recruitment of macromolecular substrates to the active site Homo sapiens
tautomycin
-
Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
cytoskeleton
-
Homo sapiens 5856
-
cytoskeleton selected PP2A enzymes are associated in an inactive state with the microtubule cytoskeleton, detailed overview Homo sapiens 5856
-
microtubule many Ser/Thr phosphatases are associated with the neuronal microtubule cytoskeleton, either directly, or indirectly through microtubule-associated proteins (MAPs). The regulated micortubule attachment of these major enzymes allows exquisite spatial modulation of MAPs phosphorylation and microtubule assembly and stability Homo sapiens 5874
-
microtubule many Ser/Thr phosphatases are associated with the neuronal microtubule cytoskeleton, either directly, or indirectly through microtubule-associated proteins (MAPs). The regulated microtubule attachment of these major enzymes allows exquisite spatial modulation of MAPs phosphorylation and microtubule assembly and stability Homo sapiens 5874
-
additional information calcineurin isoforms are compartmentalised in cells through interaction with various anchoring proteins, thereby determining substrate specificity Homo sapiens
-
-

Metals/Ions

Metals/Ions Comment Organism Structure
Ca2+ calcineurin is a calcium- and calmodulin-dependent enzyme Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
additional information Homo sapiens the PP2A/Balpha trimeric enzyme interacts with a domain encompassing the microtubule-binding repeats and upstream proline-rich region of the longest adult tau 2N/4R-Tau isoform containing 2 N-terminal inserts (2N) and four microtubule-binding repeats. PP2A is reported to be the only phosphatase mediating dephosphorylation of the neuronal phosphorylated betaIII tubulin isoform, which inhibits MAP2-stimulated microtubule assembly ?
-
?
[MAP1B protein]-serine/threonine phosphate + H2O Homo sapiens enzyme calcineurin dephosphorylates mode I sites only of MAP1B phosphorylation [MAP1B protein]-serine/threonine + phosphate
-
?
[MAP1B protein]-serine/threonine phosphate + H2O Homo sapiens enzyme PP1 dephosphorylates mode II sites only of MAP1B phosphorylation [MAP1B protein]-serine/threonine + phosphate
-
?
[MAP1B protein]-serine/threonine phosphate + H2O Homo sapiens enzyme PP2A can dephosphorylate both modes of MAP1B phosphorylation [MAP1B protein]-serine/threonine + phosphate
-
?
[MAP2 protein]-serine/threonine phosphate + H2O Homo sapiens
-
[MAP2 protein]-serine/threonine + phosphate
-
?
[tau protein]-serine/threonine phosphate + H2O Homo sapiens
-
[tau protein]-serine/threonine + phosphate
-
?
[tubulin]-serine/threonine phosphate + H2O Homo sapiens PP2A preferentially dephosphorylates unassembled tubulin [tubulin]-serine/threonine + phosphate
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens P62136 catalytic subunit alpha
-
Homo sapiens P67775 catalytic subunit alpha
-
Homo sapiens Q08209 catalytic subunit alpha
-

Source Tissue

Source Tissue Comment Organism Textmining
brain
-
Homo sapiens
-
brain calcineurin is found in many cell types, but is especially enriched in neuronal soma and processes Homo sapiens
-
neuron calcineurin is a major neuronal Ser/Thr protein phosphatase Homo sapiens
-
neuron PP1 is a major neuronal Ser/Thr protein phosphatase Homo sapiens
-
neuron PPA2 is an essential neuronal Ser/Thr protein phosphatase represents up to 1% of total cellular proteins Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
additional information the PP2A/Balpha trimeric enzyme interacts with a domain encompassing the microtubule-binding repeats and upstream proline-rich region of the longest adult tau 2N/4R-Tau isoform containing 2 N-terminal inserts (2N) and four microtubule-binding repeats. PP2A is reported to be the only phosphatase mediating dephosphorylation of the neuronal phosphorylated betaIII tubulin isoform, which inhibits MAP2-stimulated microtubule assembly Homo sapiens ?
-
?
additional information enzyme PP2A is a major tau and MAP2 phosphatase, but it can only dephosphorylate these phospho-MAPs when they are not bound to microtubules Homo sapiens ?
-
?
[MAP1B protein]-serine/threonine phosphate + H2O
-
Homo sapiens [MAP1B protein]-serine/threonine + phosphate
-
?
[MAP1B protein]-serine/threonine phosphate + H2O enzyme calcineurin dephosphorylates mode I sites only of MAP1B phosphorylation Homo sapiens [MAP1B protein]-serine/threonine + phosphate
-
?
[MAP1B protein]-serine/threonine phosphate + H2O enzyme PP1 dephosphorylates mode II sites only of MAP1B phosphorylation Homo sapiens [MAP1B protein]-serine/threonine + phosphate
-
?
[MAP1B protein]-serine/threonine phosphate + H2O enzyme PP2A can dephosphorylate both modes of MAP1B phosphorylation Homo sapiens [MAP1B protein]-serine/threonine + phosphate
-
?
[MAP2 protein]-serine/threonine phosphate + H2O
-
Homo sapiens [MAP2 protein]-serine/threonine + phosphate
-
?
[tau protein]-serine/threonine phosphate + H2O
-
Homo sapiens [tau protein]-serine/threonine + phosphate
-
?
[tubulin]-serine/threonine phosphate + H2O PP2A preferentially dephosphorylates unassembled tubulin Homo sapiens [tubulin]-serine/threonine + phosphate
-
?

Subunits

Subunits Comment Organism
More functional PP1 enzymes classically consist of a complex between the catalytic C subunit (PP1c or PPP1C, four isoforms) and one or more regulators (R or PPP1R). PP1-binding domains allow a single PP1c subunit to recruit more than one regulator, using what is described as a molecular-lego strategy. There is especially an incredible diversity of PP1-interacting proteins in the brain Homo sapiens
More the typical mammalian PP2A enzyme exists as a heterotrimer of a scaffolding A subunit (PPP2R1 A/B isoforms), a catalytic C subunit (PP2Ac or PPP2C A/B isoforms) and one of 23 regulatory B-type subunits belonging to one of 4 distinct families: B (PPP2R), B' (PPP2R5), B'' (PPP2R3) or B'''/striatins (PPP2R4). B, B' and B'' families each comprise several isoforms (named A, B, C etc. or alpha, beta, gamma etc.). Other atypical regulatory subunits, such as alpha4, can also associate with PP2Ac Homo sapiens

Synonyms

Synonyms Comment Organism
calcineurin
-
Homo sapiens
PP1
-
Homo sapiens
PPA2
-
Homo sapiens
protein phosphatase 2A
-
Homo sapiens

General Information

General Information Comment Organism
malfunction specific inhibition of calcineurin prevents axonal elongation, affects tau phosphorylation state and interferes with the establishment of cell polarity. Inhibition of PP2A, and to a lesser extent of calcineurin, enhances MAP1B phosphorylation and inhibit its microtubule binding activity Homo sapiens
malfunction specific inhibition of PP2A/Balpha is associated with enhanced tau phosphorylation, and subsequent inability of tau to bind to and stabilize microtubules. Deregulation of the microtubule cytoskeleton can in turn contribute to the inhibition of neurite outgrowth observed following silencing of PP2A/Balpha. Inhibition of PP2A, and to a lesser extent of calcineurin, enhances MAP1B phosphorylation and inhibit its microtubule binding activity Homo sapiens
metabolism multi-protein cytoskeletal scaffolds can also influence the regulation of these phosphatases, with important implications for neuronal signalling and homeostasis. Deregulation of the cytoskeletal scaffolds and phosphatase dysfunction are associated with many neurological diseases. PP2A- and PP1-dependent regulation of neurofilament architecture and regulation of the neuronal actin cytoskeleton by PP2A, PP1 and calcineurin, overview Homo sapiens
metabolism multi-protein cytoskeletal scaffolds can also influence the regulation of these phosphatases, with important implications for neuronal signalling and homeostasis. Deregulation of the cytoskeletal scaffolds and phosphatase dysfunction are associated with many neurological diseases. PP2A- and PP1-dependent regulation of neurofilament architecture, and regulation of the neuronal actin cytoskeleton by PP2A, PP1 and calcineurin, overview Homo sapiens
metabolism multi-protein cytoskeletal scaffolds can also influence the regulation of these phosphatases, with important implications for neuronal signalling and homeostasis. Deregulation of the cytoskeletal scaffolds and phosphatase dysfunction are associated with many neurological diseases. PP2A- and PP1-dependent regulation of neurofilament architecture, and regulation of the neuronal actin cytoskeleton by PP2A, PP1 and calcineurin, overview. Regulation of neurofilaments by PP2A, PP1 and calcineurin, functional significance of neurofilament (de)phosphorylation in neuronal homeostasis Homo sapiens
additional information calcineurin comprises a catalytic A or CNA subunit (PPP3C A/B/C isoforms), which interacts with calmodulin in a calcium-dependent fashion, and a regulatory B or CNB subunit (PPP3R 1/2 isoforms), which contains four calcium-binding domains. The subunits act in concert to regulate calcineurin activity Homo sapiens
additional information functional PP1 enzymes classically consist of a complex between the catalytic C subunit (PP1c or PPP1C, four isoforms) and one or more regulators (R or PPP1R). PP1-binding domains allow a single PP1c subunit to recruit more than one regulator, using what is described as a molecular-lego strategy. There is especially an incredible diversity of PP1-interacting proteins in the brain. The nearly 200 vertebrate PP1-interacting proteins identified so far show preferential docking to individual PP1 isoforms, thereby supporting PP1 functional specificity and diversity Homo sapiens
additional information the typical mammalian PP2A enzyme exists as a heterotrimer of a scaffolding A subunit (PPP2R1 A/B isoforms), a catalytic C subunit (PP2Ac or PPP2C A/B isoforms) and one of 23 regulatory B-type subunits belonging to one of 4 distinct families: B (PPP2R), B' (PPP2R5), B'' (PPP2R3) or B'''/striatins (PPP2R4). B, B' and B'' families each comprise several isoforms (named A, B, C etc. or alpha, beta, gamma etc.). Other atypical regulatory subunits, such as alpha4, can also associate with PP2Ac. PP2A activity is also regulated by many cellular regulators and natural inhibitors, such as okadaic acid. These commonly used inhibitors not only inhibit all PP2A isoforms, but also other Ser/Thr phosphatases, including PP1 and other PPP family members, at the concentrations needed to completely abrogate cellular PP2A activity Homo sapiens
physiological function the stable and dynamic subsets of microtubules are differentially regulated by protein phosphorylation-dependent mechanism. Calcineurin is a major neuronal Ser/Thr protein phosphatase playing a role in the homeostasis of the neuronal cytoskeleton. The enzyme interacts with and dephosphorylates a variety of cytoskeletal proteins, resulting in major regulation of neuronal cytoskeletal dynamics. Calcineurin is the most abundant calmodulin-binding protein in adult brain, where it plays an important role in memory and plasticity. Calcineurin is responsible for alterations in the microtubule cytoskeleton during changes in synaptic function. It also binds to tau and co-localises with tau on microtubules. Calcineurin is especially well positioned to mediate interactions between microtubule and actin cytoskeletal systems during neuritogenesis. The MAP2 protein is differentially dephosphorylated by protein phosphatases PP2A, PP1 and calcineurin. PP2A, PP1 and calcineurin dephosphorylate MAPs, thereby affecting microtubule assembly. Regulation of neurofilaments by PP2A, PP1 and calcineurin, significance of neurofilament (de)phosphorylation in neuronal homeostasis Homo sapiens
physiological function the stable and dynamic subsets of microtubules are differentially regulated by protein phosphorylation-dependent mechanism. PP1 is a major neuronal Ser/Thr protein phosphatase playing a role in the homeostasis of the neuronal cytoskeleton. The enzyme interacts with and dephosphorylates a variety of cytoskeletal proteins, resulting in major regulation of neuronal cytoskeletal dynamics. The MAP2 protein is differentially dephosphorylated by protein phosphatases PP2A, PP1 and calcineurin. PP2A, PP1 and calcineurin dephosphorylate MAPs, thereby affecting microtubule assembly. Regulation of neurofilaments by PP2A, PP1, and calcineurin, significance of neurofilament (de)phosphorylation in neuronal homeostasis Homo sapiens
physiological function the stable and dynamic subsets of microtubules are differentially regulated by protein phosphorylation-dependent mechanism. PPA2 is a major neuronal Ser/Thr protein phosphatase playing a role in the homeostasis of the neuronal cytoskeleton. The enzyme interacts with and dephosphorylates a variety of cytoskeletal proteins, resulting in major regulation of neuronal cytoskeletal dynamics. PP2A is a major tau and MAP2 phosphatase, but it can only dephosphorylate these phospho-MAPs when they are not bound to microtubules. Microtubule depolymerisation releases enzyme PP2A (and MAPs), resulting in enhanced dephosphorylation of cytosolic tubulin, tau and other MAPs like MAP2 and MAP1B. The MAP2 protein is differentially dephosphorylated by protein phosphatases PP2A, PP1 and calcineurin. PP2A, PP1 and calcineurin dephosphorylate MAPs, thereby affecting microtubule assembly Homo sapiens