A Conspicuous Connection: Structure Defines Function for the Phosphatidylinositol-Phosphate Kinase Family

Heck, Jessica N.; Mellman, David L.; Ling, Kun; Sun, Yue; Wagoner, Matthew P.; Schill, Nicholas J.; Anderson, Richard A.

doi:10.1080/10409230601162752

Cited by 91 publications

(88 citation statements)

References 170 publications

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“…It has been well characterized that PIP5K1s catalyze the production of PI(4,5)P 2 in membrane lipid metabolism (50). In terms of their cellular functions, PIP5K1s are also involved in the regulation of actin reorganization and focal adhesion dynamics, which are critical in cell migration (51) and neurite outgrowth (52,53).…”

Section: Discussionmentioning

confidence: 99%

EZH2 Regulates Neuronal Differentiation of Mesenchymal Stem Cells through PIP5K1C-dependent Calcium Signaling

Chou

Chen

et al. 2011

Journal of Biological Chemistry

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Enhancer of zeste homolog 2 (EZH2) regulates stem cells renewal, maintenance, and differentiation into different cell lineages including neuron. Changes in intracellular Ca2؉ concentration play a critical role in the differentiation of neurons. However, whether EZH2 modulates intracellular Ca 2؉ signaling in regulating neuronal differentiation from human mesenchymal stem cells (hMSCs) still remains unclear. When hMSCs were treated with a Ca 2؉ chelator or a PLC inhibitor to block IP 3 -mediated Ca 2؉ signaling, neuronal differentiation was disrupted. EZH2 bound to the promoter region of PIP5K1C to suppress its transcription in proliferating hMSCs. Interestingly, knockdown of EZH2 enhanced the expression of PIP5K1C, which in turn increased the amount of PI(4,5)P 2 , a precursor of IP 3 , and resulted in increasing the intracellular Ca 2؉ level, suggesting that EZH2 negatively regulates intracellular Ca 2؉ through suppression of PIP5K1C. Knockdown of EZH2 also enhanced hMSCs differentiation into functional neuron both in vitro and in vivo. In contrast, knockdown of PIP5K1C significantly reduced PI(4,5)P 2 contents and intracellular Ca 2؉ release in EZH2-silenced cells and resulted in the disruption of neuronal differentiation from hMSCs. Here, we provide the first evidence to demonstrate that after induction to neuronal differentiation, decreased EZH2 activates the expression of PIP5K1C to evoke intracellular Ca 2؉ signaling, which leads hMSCs to differentiate into functional neuron lineage. Activation of intracellular Ca 2؉ signaling by repressing or knocking down EZH2 might be a potential strategy to promote neuronal differentiation from hMSCs for application to neurological dysfunction diseases. Human mesenchymal stem cells (hMSCs)4 derived from bone marrow are easily obtained (1), safely expanded in vitro and are not susceptible to malignant transformation; thus, hMSCs are suitable for therapeutic applications (2). hMSCs can be induced to differentiate into multiple lineages, including bone, fat, cartilage, as well as neuron in vitro (1,(3)(4)(5). Transplanted MSCs are able to differentiate into neuronal lineage and improve the functions of central nervous system (CNS) with ischemia (6), Parkinson disease (7), Alzheimer disease (8), spinal cord injury (9, 10), and other neurodegenerative disorders (11, 12) modeled in rodents. These findings demonstrate the potential of hMSCs for cell therapy in human CNS.Spontaneous and transient elevation in intracellular Ca 2ϩ concentration during an early period is required and critical for neuronal differentiation both in vitro and in embryonic neuron development (13). However, whether intracellular Ca 2ϩ signaling is required for neuronal differentiation from hMSCs remains unclear. The expression of transient receptor potential (TRP) proteins, TRPC1 and TRPC3, is elevated to activate store-operated calcium entry (SOCE) after differentiation of H19 -7 hippocampal neuronal cells (14). It is also known that inositol 1,4,5-trisphosphate (IP 3 ) stimulates a ligand-gated chann...

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Section: Discussionmentioning

confidence: 99%

EZH2 Regulates Neuronal Differentiation of Mesenchymal Stem Cells through PIP5K1C-dependent Calcium Signaling

Chou

Chen

et al. 2011

Journal of Biological Chemistry

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“…Animal type I PIPKs direct various physiological regulations such as actin organization, vesicle trafficking, and ion channel activity at plasma membranes, whereas animal type II PIPKs, which are found only in metazoans, are localized in the cytosol, nucleus, endoplasmic reticulum, and actin cytoskeleton (Clarke et al, 2007;Heck et al, 2007). Thus, members of animal type I and type II PIPKs are thought to be functionally nonredundant, localizing to different cellular compartments.…”

Section: Discussionmentioning

confidence: 99%

“…PtdIns(4,5)P 2 is synthesized by phosphatidylinositol phosphate kinases (PIPKs; Anderson et al, 1999;Doughman et al, 2003;Heck et al, 2007). Physiological roles of several plant PIPKs have been reported.…”

mentioning

confidence: 99%

“…Rice (Oryza sativa) OsPIPK1 is proposed to be involved in shoot growth and floral initiation through the regulation of floral induction genes (Ma et al, 2004). In animals, membrane-associated type I PIPK mainly phosphorylates the D-5 hydroxyl group of PtdIns4P to produce PtdIns(4,5)P 2 but also produces PtdIns(3,4)P 2 and PtdIns(3,5)P 2 from PtdIns3P with 5-and 4-kinase activity (Anderson et al, 1999;Heck et al, 2007), whereas type II PIPK prefers the D-4 position of PtdIns5P, producing PtdIns(4,5)P 2 in the nucleus and at the endoplasmic reticulum (Clarke et al, 2007). Thus, in animals, type I and II PIPKs are involved in the generation of PtdIns(4,5)P 2 via different pathways.…”

mentioning

confidence: 99%

“…5)P 2 ] is a major PI in animal plasma membranes, affecting the localization and activity of various kinds of proteins carrying phosphatidylinositol-binding domains, which in turn affect the regulation of cytoskeletal organization, vesicle trafficking, cell proliferation, and cell growth during development and stress responses (Doughman et al, 2003;Downes et al, 2005;Di Paolo and De Camilli, 2006;Zonia and Munnik, 2006;Heck et al, 2007). In addition, PtdIns(4,5)P 2 is also a wellknown substrate of phospholipase C, producing second messengers such as diacylglycerol, phosphatidic acid (PA), and inositol-1,4,5-trisphosphate, which are involved in the activation of intracellular signal transduction pathways (Zonia and Munnik, 2006).…”

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confidence: 99%

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A Dibasic Amino Acid Pair Conserved in the Activation Loop Directs Plasma Membrane Localization and Is Necessary for Activity of Plant Type I/II Phosphatidylinositol Phosphate Kinase

et al. 2010

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Phosphatidylinositol phosphate kinase (PIPK) is an enzyme involved in the regulation of cellular levels of phosphoinositides involved in various physiological processes, such as cytoskeletal organization, ion channel activation, and vesicle trafficking. In animals, research has focused on the modes of activation and function of PIPKs, providing an understanding of the importance of plasma membrane localization. However, it still remains unclear how this issue is regulated in plant PIPKs. Here, we demonstrate that the carboxyl-terminal catalytic domain, which contains the activation loop, is sufficient for plasma membrane localization of PpPIPK1, a type I/II B PIPK from the moss Physcomitrella patens. The importance of the carboxyl-terminal catalytic domain for plasma membrane localization was confirmed with Arabidopsis (Arabidopsis thaliana) AtPIP5K1. Our findings, in which substitution of a conserved dibasic amino acid pair in the activation loop of PpPIPK1 completely prevented plasma membrane targeting and abolished enzymatic activity, demonstrate its critical role in these processes. Placing our results in the context of studies of eukaryotic PIPKs led us to conclude that the function of the dibasic amino acid pair in the activation loop in type I/II PIPKs is plant specific.

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Changing phosphoinositides “on the fly”: how trafficking vesicles avoid an identity crisis

Botelho

2009

BioEssays

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Joining an antagonistic phosphoinositide (PtdInsP) kinase and phosphatase into a single protein complex may regulate rapid and local PtdInsP changes. This may be important for processes such as membrane fission that require a specific PtdInsP and that are innately local and rapid. Such a complex could couple vesicle formation, with erasing of the identity of the donor organelle from the vesicle prior to its fusion with target organelles, thus preventing organelle identity intermixing. Coordinating signals are postulated to switch the relative activities of the kinase and phosphatase in a spatio-temporal manner that matches membrane fission events. The discovery of two such complexes supports this hypothesis. One regulates the interconversion of phosphatidylinositol and PtdIns(3)P by joining the Vps34 PtdIns 3-kinase and the myotubularin 3-phosphatases. The other regulates the interconversion between PtdIns(3)P and PtdIns(3,5)P(2) through the Fab1/PIKfyve kinase and the Fig4/mFig4 phosphatase. These lipids are essential components of the endosomal identity code.

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A Conspicuous Connection: Structure Defines Function for the Phosphatidylinositol-Phosphate Kinase Family

Cited by 91 publications

References 170 publications

EZH2 Regulates Neuronal Differentiation of Mesenchymal Stem Cells through PIP5K1C-dependent Calcium Signaling

EZH2 Regulates Neuronal Differentiation of Mesenchymal Stem Cells through PIP5K1C-dependent Calcium Signaling

A Dibasic Amino Acid Pair Conserved in the Activation Loop Directs Plasma Membrane Localization and Is Necessary for Activity of Plant Type I/II Phosphatidylinositol Phosphate Kinase

Changing phosphoinositides “on the fly”: how trafficking vesicles avoid an identity crisis

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