The Class II Phosphoinositide 3-Kinase C2α Is Activated by Clathrin and Regulates Clathrin-Mediated Membrane Trafficking

Gaidarov, Ibragim; Smith, Mary Ellen; Domin, Jan; Keen, James H.

doi:10.1016/s1097-2765(01)00191-5

Cited by 213 publications

(227 citation statements)

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“…AP2 can bind multiple PIPs, and in vitro those with D-3 phosphate increase the affinity of AP2 complexes for peptides that have internalization signals (286). This may be relevant to the observations that PtdIns3KIIC2␣ localizes in clathrin-coated pits (112) and that PtdIns(3,4,5)P 3 is important for recruitment of AP2 to activated ␤-adrenergic receptors (248). However, given the relative scarcity of PtdIns(3,4,5)P 3 , PtdIns(3,4)P 2 , and PtdIns(3)P at the plasma membrane, it is likely that PtdIns(4,5)P 2 is the major regulator of AP2 for constitutive endocytosis.…”

Section: A Ptdins(45)p 2 At the Plasma Membranementioning

confidence: 90%

“…Relatively little is known about the lipids that class II enzymes produce in vivo. However, PtdIns3KIIC2␣ is found in clathrin-coated pits at the plasma membrane and on the Golgi (80) and may play a role in membrane traffic (112). The majority of PtdIns(3)P in mammalian cells is produced by class III PI3K (363), the mammalian counterpart of Vps34p (367).…”

Section: A Pi 3-kinases and Ptdins 3-kinasesmentioning

confidence: 99%

“…PtdIns3KIIC2␣ has recently been reported to localize in clathrin-coated structures at the plasma membrane and TGN (80,112). This enzyme binds to clathrin through amino-terminal sequences, and this derepresses enzymatic activity (112).…”

Section: Ptdins3kiic2␣mentioning

confidence: 99%

“…This enzyme binds to clathrin through amino-terminal sequences, and this derepresses enzymatic activity (112). Overexpression of PtdIns3KIIC2␣ in COS cells inhibited internalization of transferrin receptors and prevented accumulation of mannose 6-phosphate receptors in the TGN, presumably by inhibiting the uncoating of clathrin-coated vesicles (112). Previously, it was observed that PtdIns(3)P and, to a lesser extent, PtdIns(3,4)P 2 enhanced the binding of AP2 adaptors to peptides containing internalization signals.…”

Section: Ptdins3kiic2␣mentioning

confidence: 99%

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Phosphoinositides in Constitutive Membrane Traffic

Roth

2004

Physiological Reviews

265

267

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Proteins that make, consume, and bind to phosphoinositides are important for constitutive membrane traffic. Different phosphoinositides are concentrated in different parts of the central vacuolar pathway, with phosphatidylinositol 4-phosphate predominate on Golgi, phosphatidylinositol 4,5-bisphosphate predominate at the plasma membrane, phosphatidylinositol 3-phosphate the major phosphoinositide on early endosomes, and phosphatidylinositol 3,5-bisphosphate found on late endocytic organelles. This spatial segregation may be the mechanism by which the direction of membrane traffic is controlled. Phosphoinositides increase the affinity of membranes for peripheral membrane proteins that function for sorting protein cargo or for the docking and fusion of transport vesicles. This implies that constitutive membrane traffic may be regulated by the mechanisms that control the activity of the enzymes that produce and consume phosphoinositides. Although the lipid kinases and phosphatases that function in constitutive membrane traffic are beginning to be identified, their regulation is poorly understood.

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Section: A Ptdins(45)p 2 At the Plasma Membranementioning

confidence: 90%

Section: A Pi 3-kinases and Ptdins 3-kinasesmentioning

confidence: 99%

Section: Ptdins3kiic2␣mentioning

confidence: 99%

Section: Ptdins3kiic2␣mentioning

confidence: 99%

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Phosphoinositides in Constitutive Membrane Traffic

Roth

2004

Physiological Reviews

265

267

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“…In these cells, PI3K-C2␣ partially colocalizes with clathrin-coated vesicles (data not shown). Because clathrin can regulate PI3K-C2␣ enzymatic activity (Gaidarov et al, 2001), PI3K-C2␣ could also be involved in the clathrin-dependent budding that is required for granule maturation . Therefore, PI3K-C2␣ may play pleiotropic roles in regulating the function of secretory and recycling vesicles in neurosecretory cells.…”

Section: Differential Sensitivity To Pi3k Inhibitors Suggest a Role Fmentioning

confidence: 99%

Phosphatidylinositol 3-Kinase C2α Is Essential for ATP-dependent Priming of Neurosecretory Granule Exocytosis

Meunier

Osborne

Hammond

et al. 2005

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102

108

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Neurotransmitter release and hormonal secretion are highly regulated processes culminating in the calcium-dependent fusion of secretory vesicles with the plasma membrane. Here, we have identified a role for phosphatidylinositol 3-kinase C2␣ (PI3K-C2␣) and its main catalytic product, PtdIns3P, in regulated exocytosis. In neuroendocrine cells, PI3K-C2␣ is present on a subpopulation of mature secretory granules. Impairment of PI3K-C2␣ function specifically inhibits the ATP-dependent priming phase of exocytosis. Overexpression of wild-type PI3K-C2␣ enhanced secretion, whereas transfection of PC12 cells with a catalytically inactive PI3K-C2␣ mutant or a 2xFYVE domain sequestering PtdIns3P abolished secretion. Based on these results, we propose that production of PtdIns3P by PI3K-C2␣ is required for acquisition of fusion competence in neurosecretion. INTRODUCTIONThe analysis of the molecular mechanism controlling neuroexocytosis has been greatly helped by studies on neurosecretory cells (Dunn and Holz, 1983;Sarafian et al., 1987;Martin and Walent, 1989;Monck and Fernandez, 1994;Rettig and Neher, 2002). Early work has shed light on two major steps consisting of the reversible ATP-dependent priming of docked granules followed by their Ca 2ϩ -driven fusion with the plasma membrane and release of the granule content (Holz et al., 1989;Hay and Martin, 1992). The spatiotemporal control of intracellular Ca 2ϩ concentration together with capacitance measurements has allowed the identification of distinct pools of chromaffin granules involved in these distinct steps (Rettig and Neher, 2002). Further electrophysiological and biochemical approaches, such as the reconstitution of secretion in permeabilized neurosecretory cells (Martin and Walent, 1989), have highlighted the role of key factors involved in these two processes. Cytosolic and membrane proteins have been linked to priming and fusion, including the mammalian orthologues of the Caenorhabditis elegans UNC13 and UNC18 gene products, synaptotagmins, and members of the SNARE family and associated proteins (Jahn and Sudhof, 1999;Burgoyne et al., 2001;Brose and Rosenmund, 2002;Rettig and Neher, 2002).In contrast, less is known about the contribution of lipid dynamics during these processes with the exception of phosphatidic acid and phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P 2 ]. The former is produced by phospholipase D, which is essential for secretion in neurons (Humeau et al., 2001) and in neuroendocrine cells . The inhibition of Ca 2ϩ -dependent catecholamine release after depletion of phosphatidylinositol highlighted the role of phosphoinositides during the secretory events (Eberhard et al., 1990). Moreover, phosphatidylinositol transfer protein and phosphatidylinositol-4-phosphate 5 kinase (PI4P5K) were shown to be required for the ATP-dependent priming of secretory granules in PC12 cells (Hay and Martin, 1993;Hay et al., 1995). In addition, phosphatidylinositol 4-kinase (PI4K), an integral membrane protein of chromaffin granules and synaptic vesicles, is r...

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Transcriptional response of dermal fibroblasts in direct current electric fields

Jennings

Chen

Feldman

2008

Bioelectromagnetics

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During the course of normal wound healing, fibroblasts at the wound edge are exposed to electric fields (EFs) ranging from 40 to 200 mV/mm. Various forms of EFs influence fibroblast migration, proliferation, and protein synthesis. Thus, EFs may contribute to fibroblast activation during wound repair. To elucidate the role of EFs during the normal progression of healing, this study compares gene expression in normal adult dermal fibroblasts exposed to a 100 mV/mm EF for 1 h to non-stimulated controls. Significantly increased expression of 162 transcripts and decreased expression of 302 transcripts was detected using microarrays, with 126 transcripts above the level of 1.4-fold increases or decreases compared to the controls. Above the level of twofold, only 11 genes were significantly increased or decreased compared to controls. Many of these significantly regulated genes are associated with wound repair through the processes of matrix production, cellular signaling, and growth. Activity within specific cellular signaling pathways is noted, including TGF-beta, G-proteins, and inhibition of apoptosis. In addition, RT-PCR analysis of the expression of KLF6, FN1, RGS2, and JMJD1C over continued stimulation and at different field strengths suggests that there are specific windows of field characteristics for maximum induction of these genes. EFs thus appear to have an important role in controlling fibroblast activity in the process of wound healing.

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The Class II Phosphoinositide 3-Kinase C2α Is Activated by Clathrin and Regulates Clathrin-Mediated Membrane Trafficking

Cited by 213 publications

References 49 publications

Phosphoinositides in Constitutive Membrane Traffic

Phosphoinositides in Constitutive Membrane Traffic

Phosphatidylinositol 3-Kinase C2α Is Essential for ATP-dependent Priming of Neurosecretory Granule Exocytosis

Transcriptional response of dermal fibroblasts in direct current electric fields

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