Movin' on up: the role of PtdIns(4,5)P2 in cell migration

Ling, Kun; Schill, Nicholas J.; Wagoner, Matthew P.; Sun, Yue; Anderson, Richard A.

doi:10.1016/j.tcb.2006.03.007

Cited by 131 publications

(179 citation statements)

References 77 publications

Supporting

Mentioning

177

Contrasting

Order By: Relevance

“…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). Among all PIP5K1s, PIP5K1C is mainly expressed in brain and required for cardiovascular and neuronal development.…”

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

View full text Add to dashboard Cite

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...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…GTPases of the Rho family and Arf6 stimulate the production of PI(4,5)P 2 via type I␣ PIP 5-kinase (reviewed in Ling et al, 2006 andSantarius et al, 2006). Using FRET-based biosensors for GTPases, we and others have found that the activities of RhoA, Rac1, and Cdc42 are increased toward the leading edge of migrating cells (Kraynov et al, 2000;Itoh et al, 2002;Nalbant et al, 2004;Kurokawa and Matsuda, 2005).…”

Section: Discussionmentioning

confidence: 99%

Rapid Turnover Rate of Phosphoinositides at the Front of Migrating MDCK Cells

Nishioka

Aoki

Hikake

et al. 2008

MBoC

View full text Add to dashboard Cite

Phosphoinositides (PtdInss) play key roles in cell polarization and motility. With a series of biosensors based on Fö rster resonance energy transfer, we examined the distribution and metabolism of PtdInss and diacylglycerol (DAG) in stochastically migrating Madin-Darby canine kidney (MDCK) cells. The concentrations of phosphatidylinositol (4,5)-bisphosphate, phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), phosphatidylinositol (3,4)-bisphosphate, and DAG were higher at the plasma membrane in the front of the cell than at the plasma membrane of the rear of the cell. The difference in the concentrations of PtdInss was estimated to be less than twofold between the front and rear of the migrating MDCK cells. To decode the spatial activities of PtdIns metabolic enzymes from the obtained concentration maps of PtdInss, we developed a one-dimensional reaction diffusion model of PtdIns metabolism. In this model, the activities of phosphatidylinositol monophosphate 5-kinase, phosphatidylinositol 3-kinase, phospholipase C, and PIP 3 5-phosphatases were higher at the plasma membrane of the front than at the plasma membrane of the rear of the cell. This result suggests that, although the difference in the steady-state level of PtdInss is less than twofold, PtdInss were more rapidly turned over at the front than the rear of the migrating MDCK cells. INTRODUCTIONCell migration is an important event during early development, inflammatory responses to infection, and wound healing, and it is an important pathological event during tumor invasion and metastasis. Despite morphological and functional differences, different migratory cells share a conserved set of polarity signals. Kinases for phosphoinositides (PtdInss), Rho GTPases, and the actin and microtubule cytoskeletons play key roles in signaling polarity in cells ranging from Dictyostelium discoideum (Charest and Firtel, 2006) to neurons (Luo, 2000;Aoki et al., 2007) and neutrophils (Van Keymeulen et al., 2006;Wong et al., 2006).PtdInss are a family of phospholipids containing myoinositol as their head group (reviewed in Takenawa and Itoh, 2001). Despite a relatively low abundance in biological membranes, PtdInss have been reported to regulate a myriad of cellular processes. Among them, phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P 2 ] is the major PtdInss at the inner leaflet of the plasma membrane. On growth factor stimulation, intracellular second messengers such as inositol (1,4,5)-trisphosphate (IP 3 ), diacylglycerol (DAG), and phosphatidylinositol (3,4,5)-triphosphate (PIP 3 ) are generated from PI(4,5)P 2 .The discovery that the pleckstrin homology (PH) domain in the signaling proteins recognizes specific phosphoinositides revealed that stimulated proteins translocate to specific regions of the membrane to participate in signaling events via interaction with these lipids (reviewed in Di Paolo and De Camilli, 2006). A series of experiments indicated that the PH domains from different proteins recognize different PtdInss and led to the development of a novel t...

show abstract

“…Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] regulates cell motility, cell shape, vesicle turnover, and membrane excitability either through directly binding to target proteins (1)(2)(3) or by mediating calcium signaling via its cleavage by phospholipase C into inositol 1,4,5-trisphosphate and diacylglycerol (4). Phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] regulates cell proliferation, survival, and morphology (5).…”

mentioning

confidence: 99%

“…Recently, we identified a phosphoinositide phosphatase, Ciona intestinalis voltage sensor-containing phosphatase (Ci-VSP), consisting of an ion channel-like transmembrane domain followed by a phosphatase domain which shares sequence identity to the phosphatase and tensin homolog deleted on chromosome 10q23 (PTEN). PTEN is a well characterized PI phosphatase that dephosphorylates the phosphate on the 3Ј position of PI(3,4,5)P 3 , resulting in generation of PI(4,5)P 2 (6,7). Ci-VSP shares overlapping substrate specificity with PTEN in that it was also shown to dephosphorylate PI(3,4,5)P 3 (8).…”

mentioning

confidence: 99%

A voltage-sensing phosphatase, Ci-VSP, which shares sequence identity with PTEN, dephosphorylates phosphatidylinositol 4,5-bisphosphate

Iwasaki

Murata

Kim

et al. 2008

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

126

209

View full text Add to dashboard Cite

phosphoinositide ͉ PI(4,5)P2 ͉ voltage sensor ͉ PI(3,4,5)P3 ͉ substrate specificity P hosphatidylinositol (PI) lipids serve structural roles in biological membranes as well as playing important roles as signaling molecules. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] regulates cell motility, cell shape, vesicle turnover, and membrane excitability either through directly binding to target proteins (1-3) or by mediating calcium signaling via its cleavage by phospholipase C into inositol 1,4,5-trisphosphate and diacylglycerol (4). Phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] regulates cell proliferation, survival, and morphology (5). To exert physiological roles, the concentrations of these phosphoinositides in membranes are strictly regulated by multiple kinases and phosphatases. Recently, we identified a phosphoinositide phosphatase, Ciona intestinalis voltage sensor-containing phosphatase (Ci-VSP), consisting of an ion channel-like transmembrane domain followed by a phosphatase domain which shares sequence identity to the phosphatase and tensin homolog deleted on chromosome 10q23 (PTEN). PTEN is a well characterized PI phosphatase that dephosphorylates the phosphate on the 3Ј position of PI(3,4,5)P 3 , resulting in generation of PI(4,5)P 2 (6, 7). Ci-VSP shares overlapping substrate specificity with PTEN in that it was also shown to dephosphorylate PI(3,4,5)P 3 (8).A voltage-gated ion channel commonly consists of two parts: the N terminus (S1 to S4) functions as a voltage sensor while the C terminus (S5 to S6) functions as an ion-permeable pore (9). The transmembrane region of Ci-VSP shows significant sequence homology to the voltage-sensor domains of the conventional voltage-gated channels but does not contain the pore domain. Basic amino acids spaced periodically in the fourth transmembrane segments (S4) are known to be essential for sensing changes in the membrane potential in voltage-gated ion channels (8,9). This pattern of basic amino acids is also conserved in the fourth transmembrane segment (S4) of Ci-VSP. Indeed, Xenopus oocytes injected with Ci-VSP cRNA showed transient ''gating'' currents as the readouts of the movement of S4 across the membrane in response to voltage change, demonstrating that the N terminus of Ci-VSP functions as a voltage sensor (8).We hypothesized that the voltage-sensor domain of Ci-VSP could potentially regulate the activity of the phosphatase domain. Along these lines we were able to demonstrate that the activity of the PI(4,5)P 2 -sensitive potassium channel coexpressed with Ci-VSP increases at hyperpolarization and decreases at depolarization (8). This result cannot be reconciled with the known enzymatic activity of Ci-VSP, which would result in increased PI(4,5)P 2 levels, thereby resulting only in activation of the potassium channel. In addition, confocal imaging of pleckstrin homology domains (PHDs) fused to GFP as detectors of PI(4,5)P 2 and PI(3,4,5)P 3 , as well as electrophysiological measurements of potassium currents in Xenopus oocytes, showed th...

show abstract

Movin' on up: the role of PtdIns(4,5)P2 in cell migration

Cited by 131 publications

References 77 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

Rapid Turnover Rate of Phosphoinositides at the Front of Migrating MDCK Cells

A voltage-sensing phosphatase, Ci-VSP, which shares sequence identity with PTEN, dephosphorylates phosphatidylinositol 4,5-bisphosphate

Contact Info

Product

Resources

About