Paladin is a phosphoinositide phosphatase regulating endosomal VEGFR2 signalling and angiogenesis

Elevation of amyloid β-peptide (Aβ) is critically associated with Alzheimer disease (AD) pathogenesis. Aβ-induced synaptic abnormalities, including altered receptor trafficking and synapse loss, have been linked to cognitive deficits in AD. Recent work implicates a lipid critical for neuronal function, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], in Aβ-induced synaptic and behavioral impairments. Synaptojanin 1 (Synj1), a lipid phosphatase mediating the breakdown of PI(4,5)P2, has been shown to play a role in synaptic vesicle recycling and receptor trafficking in neurons. Heterozygous deletion of Synj1 protected neurons from Aβ-induced synaptic loss and restored learning and memory in a mouse model of AD. Thus, inhibition of Synj1 may ameliorate Aβ-associated impairments, suggesting Synj1 as a potential therapeutic target. To this end, we developed a screening assay for Synj1 based on detection of inorganic phosphate liberation from a water-soluble, short-chain PI(4,5)P2. The assay displayed saturable kinetics and detected Synj1’s substrate preference for PI(4,5)P2 over PI(3,4,5)P3. The assay will enable identification of novel Synj1 inhibitors that have potential utility as chemical probes to dissect the cellular role of Synj1 as well as potential to prevent or reverse AD-associated synaptic abnormalities.

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Differential Role of PTEN Phosphatase in Chemotactic Growth Cone Guidance

Journal of Biological Chemistry ◽

10.1074/jbc.c113.487066 ◽

2013 ◽

Vol 288 (29) ◽

pp. 20837-20842 ◽

Cited By ~ 12

Author(s):

Steven J. Henle ◽

Lucas P. Carlstrom ◽

Thomas R. Cheever ◽

John R. Henley

Keyword(s):

Growth Cone ◽

Essential Feature ◽

Pten Expression ◽

Spinal Neurons ◽

Phosphoinositide Phosphatase ◽

Integrin Clustering ◽

Myelin Associated Glycoprotein ◽

Phosphatase And Tensin Homologue ◽

Regenerative Therapies

Negatively targeting the tumor suppressor and phosphoinositide phosphatase PTEN (phosphatase and tensin homologue) promotes axon regrowth after injury. How PTEN functions in axon guidance has remained unknown. Here we report the differential role of PTEN in chemotactic guidance of axonal growth cones. Down-regulating PTEN expression in Xenopus laevis spinal neurons selectively abolished growth cone chemorepulsion but permitted chemoattraction. These findings persisted during cAMP-dependent switching of turning behaviors. Live cell imaging using a GFP biosensor revealed rapid PTEN-dependent depression of phosphatidylinositol 3,4,5-trisphosphate levels in the growth cone induced by the repellent myelin-associated glycoprotein. Moreover, down-regulating PTEN expression blocked negative remodeling of β1-integrin adhesions triggered by myelin-associated glycoprotein, yet permitted integrin clustering by a positive chemotropic treatment. Thus, PTEN negatively regulates growth cone phosphatidylinositol 3,4,5-trisphosphate levels and mediates chemorepulsion, whereas chemoattraction is PTEN-independent. Regenerative therapies targeting PTEN may therefore suppress growth cone repulsion to soluble cues while permitting attractive guidance, an essential feature for re-forming functional neural circuits.

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Differences in signaling pathways and expression level of the phosphoinositide phosphatase SHIP1 between two oncogenic mutants of the receptor tyrosine kinase KIT

Cellular Signalling ◽

10.1016/j.cellsig.2005.06.008 ◽

2006 ◽

Vol 18 (5) ◽

pp. 661-669 ◽

Cited By ~ 10

Author(s):

J.M. Vanderwinden ◽

D. Wang ◽

N. Paternotte ◽

S. Mignon ◽

K. Isozaki ◽

...

Keyword(s):

Tyrosine Kinase ◽

Signaling Pathways ◽

Receptor Tyrosine Kinase ◽

Expression Level ◽

Phosphoinositide Phosphatase

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Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML

Blood ◽

10.1182/blood-2014-09-603555 ◽

2015 ◽

Vol 125 (18) ◽

pp. 2815-2824 ◽

Cited By ~ 27

Author(s):

Sewa Rijal ◽

Shaun Fleming ◽

Nik Cummings ◽

Natalie K. Rynkiewicz ◽

Lisa M. Ooms ◽

...

Keyword(s):

Inositol Polyphosphate ◽

Poor Outcome ◽

Phosphoinositide Phosphatase ◽

Key Points

Key Points INPP4B promotes chemoresistance in AML independent of phosphoinositide phosphatase function.

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The phosphoinositide phosphatase Sac1 regulates cell shape and microtubule stability in the developingDrosophilaeye

Development ◽

10.1242/dev.151571 ◽

2018 ◽

Vol 145 (11) ◽

pp. dev151571 ◽

Cited By ~ 1

Author(s):

Lauren M. Del Bel ◽

Nigel Griffiths ◽

Ronit Wilk ◽

Ho-Chun Wei ◽

Anastasia Blagoveshchenskaya ◽

...

Keyword(s):

Cell Shape ◽

Microtubule Stability ◽

Phosphoinositide Phosphatase

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Polyunsaturated Fatty Acids Influence Synaptojanin Localization to Regulate Synaptic Vesicle Recycling

Molecular Biology of the Cell ◽

10.1091/mbc.e07-07-0719 ◽

2008 ◽

Vol 19 (3) ◽

pp. 833-842 ◽

Cited By ~ 39

Author(s):

Esther Marza ◽

Toni Long ◽

Adolfo Saiardi ◽

Marija Sumakovic ◽

Stefan Eimer ◽

...

Keyword(s):

Fatty Acids ◽

Polyunsaturated Fatty Acids ◽

Synaptic Vesicle ◽

Synaptic Vesicles ◽

Endocytic Pathway ◽

Synaptic Membranes ◽

Synaptic Vesicle Recycling ◽

Vesicle Recycling ◽

Phosphoinositide Phosphatase ◽

Low Levels

The lipid polyunsaturated fatty acids are highly enriched in synaptic membranes, including synaptic vesicles, but their precise function there is unknown. Caenorhabditis elegans fat-3 mutants lack long-chain polyunsaturated fatty acids (LC-PUFAs); they release abnormally low levels of serotonin and acetylcholine and are depleted of synaptic vesicles, but the mechanistic basis of these defects is unclear. Here we demonstrate that synaptic vesicle endocytosis is impaired in the mutants: the synaptic vesicle protein synaptobrevin is not efficiently retrieved after synaptic vesicles fuse with the presynaptic membrane, and the presynaptic terminals contain abnormally large endosomal-like compartments and synaptic vesicles. Moreover, the mutants have abnormally low levels of the phosphoinositide phosphatase synaptojanin at release sites and accumulate the main synaptojanin substrate phosphatidylinositol 4,5-bisphosphate at these sites. Both synaptobrevin and synaptojanin mislocalization can be rescued by providing exogenous arachidonic acid, an LC-PUFA, suggesting that the endocytosis defect is caused by LC-PUFA depletion. By showing that the genes fat-3 and synaptojanin act in the same endocytic pathway at synapses, our findings suggest that LC-PUFAs are required for efficient synaptic vesicle recycling, probably by modulating synaptojanin localization at synapses.

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Targeting of PKCζ and PKB to caveolin-enriched microdomains represents a crucial step underpinning the disruption in PKB-directed signalling by ceramide

Biochemical Journal ◽

10.1042/bj20070936 ◽

2008 ◽

Vol 410 (2) ◽

pp. 369-379 ◽

Cited By ~ 78

Author(s):

Eric Hajduch ◽

Sophie Turban ◽

Xavier Le Liepvre ◽

Soazig Le Lay ◽

Christopher Lipina ◽

...

Keyword(s):

Protein Kinase ◽

Structural Integrity ◽

Insulin Signalling ◽

Protein Kinase B ◽

Cholesterol Depletion ◽

Crucial Step ◽

Caveolin 1 ◽

Kinase C ◽

Phosphoinositide Phosphatase ◽

Phosphatase And Tensin Homologue

Elevated ceramide concentrations in adipocytes and skeletal muscle impair PKB (protein kinase B; also known as Akt)-directed insulin signalling to key hormonal end points. An important feature of this inhibition involves the ceramide-induced activation of atypical PKCζ (protein kinase C-ζ), which associates with and negatively regulates PKB. In the present study, we demonstrate that this inhibition is critically dependent on the targeting and subsequent retention of PKCζ–PKB within CEM (caveolin-enriched microdomains), which is facilitated by kinase interactions with caveolin. Ceramide also recruits PTEN (phosphatase and tensin homologue detected on chromosome 10), a 3′-phosphoinositide phosphatase, thereby creating a repressive membrane microenvironment from which PKB cannot signal. Disrupting the structural integrity of caveolae by cholesterol depletion prevented caveolar targeting of PKCζ and PKB and suppressed kinase–caveolin association, but, importantly, also ameliorated ceramide-induced inhibition of PKB. Consistent with this, adipocytes from caveolin-1−/− mice, which lack functional caveolae, exhibit greater resistance to ceramide compared with caveolin-1+/+ adipocytes. We conclude that the recruitment and retention of PKB within CEM contribute significantly to ceramide-induced inhibition of PKB-directed signalling.

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