Fostriecin, an antitumor antibiotic with inhibitory activity against serine/threonine protein phosphatases types 1 (PP1) and 2A (PP2A), is highly selective for PP2A

Walsh, Aimée H.; Cheng, Aiyang; Honkanen, Richard E.

doi:10.1016/s0014-5793(97)01210-6

Cited by 201 publications

(178 citation statements)

References 40 publications

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“…To verify that PP-2A inhibitors were used at saturating concentration, 10, 30, and 60 M cytostatin was tested, and no differences were observed in time course or magnitude of depression (data not shown). At these concentrations, both fostriecin and cytostatin block PP-2A [EC 50 Ͻ5 nM and Ͻ100 nM, respectively (35,36), see also Fig. 6, which is published as supporting information on the PNAS web site], but do not affect PP-1, PP-5, PP-2B, or PP-2C.…”

Section: Resultsmentioning

confidence: 99%

Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor

Lavstsen

Endo

Sakai

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Section: Resultsmentioning

confidence: 99%

Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor

Lavstsen

Endo

Sakai

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, it appeared that the dephosphorylation was mediated by PP1 and/or PP2A. To define the subtype of protein phosphatase involved, a novel and more specific inhibitor of PP2A, fostriecin (IC 50 ϭ 3.2 nM) (20), was utilized in additional phosphorylation studies. As illustrated in Fig.…”

Section: Fig 2 Marcks Protein Is a Key Component Of The Mucin Secrementioning

confidence: 99%

MARCKS Protein Is a Key Molecule Regulating Mucin Secretion by Human Airway Epithelial Cells in Vitro

Li¹,

Martin²,

Spizz³

et al. 2001

Journal of Biological Chemistry

160

186

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Hypersecretion of airway mucin characterizes numerous respiratory diseases. Although diverse pathological stimuli can provoke exocytotic release of mucin from secretory cells of the airway epithelium, mechanisms involved remain obscure. This report describes a new paradigm for the intracellular signaling mechanism regulating airway mucin secretion. Direct evidence is provided that the myristoylated alanine-rich C kinase substrate (MARCKS) is a central regulatory molecule linking secretagogue stimulation at the cell surface to mucin granule release by differentiated normal human bronchial epithelial cells in vitro. Down-regulation of MARCKS expression or disruption of MARCKS function in these cells inhibits the secretory response to subsequent stimulation. The intracellular mechanism controlling this secretory process involves cooperative action of two separate protein kinases, protein kinase C and cGMP-dependent protein kinase. Upon stimulation, activated protein kinase C phosphorylates MARCKS, causing translocation of MARCKS from the plasma membrane to the cytoplasm, where it is then dephosphorylated by a protein phosphatase 2A that is activated by cGMP-dependent protein kinase, and associates with both actin and myosin. Dephosphorylated cytoplasmic MARCKS would also be free to interact with mucin granule membranes and thus could link granules to the contractile cytoskeleton, mediating their movement to the cell periphery and subsequent exocytosis. These findings suggest several novel intracellular targets for pharmacological intervention in disorders involving aberrant secretion of respiratory mucin and may relate to other lesions involving exocytosis of membrane-bound granules in various cells and tissues.

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“…Cross-assay comparisons are particularly interesting since IC 50 values for fostriecin inhibition of PP2A are not only dependent on the assay enzyme concentration, but also the phosphorylated substrate used in the assay. 7,9 In preceding efforts related to the fostriecin family of natural products, we determined the stereochemical configuration of fostriecin (2) and reported its first total synthesis. 10 Subsequent to this work, a number of additional synthetic efforts have been described including eight total or formal syntheses of 2, each highlighting the utility of alternative asymmetric synthetic methods for the construction of the 4 chiral centers of 2 in a stereoselective manner.…”

Section: Introductionmentioning

confidence: 99%

Total Synthesis and Evaluation of Cytostatin, Its C10−C11 Diastereomers, and Additional Key Analogues: Impact on PP2A Inhibition

et al. 2006

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The total synthesis of cytostatin, an antitumor agent belonging to the fostriecin family of natural products is described in full detail. The convergent approach relied on a key epoxide opening reaction to join the two stereotriad units and a single-step late stage, stereoselective installation of the sensitive (Z,Z,E)-triene through a β-chelation controlled nucleophilic addition. The synthetic route provided rapid access to the C4-C6 stereoisomers of the cytostatin lactone, which were prepared and used to define the C4-C6 relative stereochemistry of the natural product. In addition to the natural product, each of the C10-C11 diastereomers of cytostatin was divergently prepared (11 steps from key convergence step) by this route and used to unequivocally confirm the relative and absolute stereochemistry of cytostatin. Each of the cytostatin diastereomers exhibited a reduced activity towards inhibition of PP2A (>100-fold), demonstrating the importance of the presence and stereochemistry of the C10-methyl and C11-hydroxy groups for potent PP2A inhibition. Extensions of the studies provided dephosphocytostatin (40), sulfocytostatin (67, a key analogue related to the natural product sultriecin), 11-deshydroxycytostatin (78), and 72 lacking the entire C12-C18 (Z,Z,E)-triene segment and were used to define the magnitude of the C9-phosphate (>4000-fold), C11-alcohol (250-fold), and triene (220-fold) contribution to PP2A inhibition. A model of cytostatin bound to the active site of PP2A is presented, compared to that of fostriecin which is also presented in detail for the first time, and used to provide insights into the role of the key substituents. Notably, the α,β-unsaturated lactone of cytostatin, like that of fostriecin, is projected to serve as a key electrophile providing a covalent adduct with Cys269 unique to PP2A contributing to its potency (≥200-fold for fostriecin) and accounting for its selectivity.

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Fostriecin, an antitumor antibiotic with inhibitory activity against serine/threonine protein phosphatases types 1 (PP1) and 2A (PP2A), is highly selective for PP2A

Cited by 201 publications

References 40 publications

Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor

Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor

MARCKS Protein Is a Key Molecule Regulating Mucin Secretion by Human Airway Epithelial Cells in Vitro

Total Synthesis and Evaluation of Cytostatin, Its C10−C11 Diastereomers, and Additional Key Analogues: Impact on PP2A Inhibition

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