Chan-Soo Lee

Phosphorylation of RhoGDI1 by p21-activated kinase 2 mediates basic fibroblast growth factor-stimulated neurite outgrowth in PC12 cells.

We previously showed that p21-activated kinase 2 (PAK2), a major PAK isoform expressed in PC12 cells, mediates neurite outgrowth via Rac1 GTPase. RhoGDI1 forms a complex with Rac1, resulting in its inhibition. Rac1 activation requires dissociation from RhoGDI1. Here, we show that PAK2 mediates basic fibroblast growth factor (bFGF)-stimulated neurite outgrowth via phosphorylation of RhoGDI1. RhoGDI1 was shown to be associated with PAK2, with phosphorylation of Ser34 and Ser101 by active PAK2 evident in vitro and in vivo. A RhoGDI1 phosphomimetic mutant (S34E/S101E) was dissociated from Rac1/Cdc42, whereas the wild-type or a nonphosphorylatable mutant (S34A/S101A) formed a tight complex. Consistent with this, PC12 cells expressing the phosphomimetic mutant displayed Rac1/Cdc42 activation in response to bFGF stimulation. Neurite outgrowth was also enhanced in PC12 cells expressing the phosphomimetic mutant. These results suggest that PAK2-mediated RhoGDI1 phosphorylation stimulates dissociation of RhoGDI1-Rac1/Cdc42 complex accompanied by relief of inhibitory effect on Rac1/Cdc42, which promotes neuronal differentiation.

Integrated BiCMOS Control Circuits for High-Performance DC–DC Boost Converter

This paper introduces the design of integrated BiCMOS current-sensing circuit and amplifier for high-performance current-mode dc-dc boost converter. By exploiting the advantage presented by the integration of both CMOS and bipolar devices within same technology, the BiCMOS circuits offers high-gain amplifier and accurately sensed inductor current. The error amplifier has BJT differential pair and current sources to obtain a fast response, while the current-sensing circuit exploits a current-mirror instead of opamplifier as a voltage follower. The test in 0.35-μm BiCMOS process shows that the transient time of the error amplifier is about 4 μs and the current-sensing circuit can operate with accuracy of 88% at the frequency of 20 kHz. The output voltage of 4.8-8 V is obtained at the input voltage of 3-5 V with the ripple ratio within 5%.

Phosphorylation of β-catenin at serine 663 regulates its transcriptional activity.

β-Catenin, a component of Wnt signaling, plays a key role in colorectal carcinogenesis. The phosphorylation status of β-catenin determines its fate and affects its cellular function, and serine 675 (S675) was previously identified as a common target of p21-activated kinase 1 (PAK1) and protein kinase A. In the present study, we explored the PAK1-specific phosphorylation site(s) in β-catenin. Active PAK1 T423E but not inactive PAK1 K299R interacted with and phosphorylated β-catenin. Mutagenesis followed by a kinase assay revealed that PAK1 phosphorylated S663 in addition to S675, and an anti-phospho-β-catenin(S663) antibody detected the phosphorylation of S663 downstream of PAK1 in various human colon cancer cells. Furthermore, the Wnt3a-stimulated S663 phosphorylation was inhibited by the PAK1-specific inhibitor, IPA-3, but not by H-89 or LY294002. The non-phosphorylatable mutant forms of β-catenin, S663A, S675A and S663/675A, showed similar defects in their PAK1-induced TCF/LEF transactivation, whereas the phosphomimetic form of β-catenin, S663D, demonstrated a transcriptional activity that was comparable to that of β-catenin S675D and β-catenin S663D/S675D. Taken together, these results provide evidence that PAK1 specifically phosphorylates β-catenin at S663 and that this phosphorylation is essential for the PAK1-mediated transcriptional activation of β-catenin.

Integrated on-chip 0.35 μm BiCMOS current-mode DC–DC buck converter

A current-mode DC–DC buck converter with a fully integrated power module is presented in this article. The converter is implemented using BiCMOS technology in amplifier and power MOSFET in a current sensor. The current sensor is realised by the power lateral double-diffused MOSFET with the aspect ratio much larger than that of a matched p-MOSFET. In addition, BiCMOS technology is applied in the error amplifier for an accurate current sensing and a fast transient response. The DC–DC converter is fabricated with 0.35 µm BiCMOS process. Experimental results show that the fully integrated converter operates at 1.3 MHz switching frequency with a supply voltage of 5 V. The output DC voltage is obtained as expected and the output ripple is controlled to be within 2% with a 30 µH off-chip inductor and 100 µF off-chip capacitor.

Involvement of βPIX in angiotensin II-induced migration of vascular smooth muscle cells

Angiotensin II (Ang II) stimulates migration of vascular smooth muscle cell (VSMC) in addition to its contribution to contraction and hypertrophy. It is well established that Rho GTPases regulate cellular contractility and migration by reorganizing the actin cytoskeleton. Ang II activates Rac1 GTPase, but its upstream guanine nucleotide exchange factor (GEF) remains elusive. Here, we show that Ang II-induced VSMC migration occurs in a βPIX GEF-dependent manner. βPIX-specific siRNA treatment significantly inhibited Ang II-induced VSMC migration. Ang II activated the catalytic activity of βPIX towards Rac1 in dose- and time-dependent manners. Activity reached a peak at 10 min and declined close to a basal level by 30 min following stimulation. Pharmacological inhibition with specific kinase inhibitors revealed the participation of protein kinase C, Src family kinase, and phosphatidylinositol 3-kinase (PI3-K) upstream of βPIX. Both p21-activated kinase and reactive oxygen species played key roles in cytoskeletal reorganization downstream of βPIX-Rac1. Taken together, our results suggest that βPIX is involved in Ang II-induced VSMC migration.

Effect of MIM and n-Well Capacitors on Programming Characteristics of EEPROM

During the 1980s, a novel nonvolatile memory product was introduced, referred to as flash electrically erasable program-mable read-only memory (EEPROM). The basic operating prin-ciple of the nonvolatile memory device is to store charges in the gate oxide of a metal-oxide semiconductor field-effect transistor (MOSFET). If charges can be stored in the oxide of a MOSFET, the threshold voltage of the MOSFET can be modified to switch between two distinct values, conventionally defined as the erase state and the program state. The terms erase and program are used to denote operations that charge and discharge through ox-ide. The threshold voltage shift between the two states is caused by the storage of charge in oxide. The program state is usually obtained from a channel hot electron, while the erase state uses Fowler-Nordheim (F-N) tunneling through a thin gate oxide. The storage of charges in the gate oxide of the nonvolatile memory device can be realized by surrounding a conducting layer by an oxide. Since this layer acts as a completely electrically isolated gate, this type of device is commonly referred to as a floating gate device.An EEPROM cell containing an n-well and metal-insulator-metal (MIM) capacitor was fabricated using a 0.18 μm stan-dard complementary MOS (CMOS) process. In recent efforts, a stacked metal-insulator-metal (MIM) and an n-well capacitor have been applied to a single polysilicon EEPROM cell in order to increase memory capacity [1-4]. The application of the single polysilicon EEPROM is becoming more popular due to its low process cost and satisfactory reliability [5-7]. Optimal charac-teristics of EEPROM include fast program/erase speed, high endurance performance, and low leakage current. Although the MIM capacitor cell performs well, it requires a large device-size. The n-well control gate cell inherently possesses high junction capacitance and high sheet resistance. In this paper, we propose an EEPROM cell that does not re-quire additional cell area in order to obtain a high capacitance. Additionally, the proposed EEPROM provided a satisfactory control gate coupling ratio contributing to the junction capaci-tance between the control gate and the n-well. Because the n-well depletion capacitor was isolated by shallow trench iso-lation (STI) and the MIM capacitor was located just above the n-well capacitor, the cell containing two capacitors connected in parallel was expected to be very reliable and to provide noise immunity.

A low‐power CMOS DC‐DC buck converter with on‐chip stacked spiral inductor

Purpose – The purpose of this paper is to present a fully integrated power converter. A stacked spiral inductor is applied in a voltage‐mode CMOS DC‐DC converter for the chip miniaturization and low‐power operation.Design/methodology/approach – The three‐layer spiral inductor is simulated with an equivalent circuit and applied to the DC‐DC converter. The DC‐DC buck converter has been fabricated with a standard 0.35 μm CMOS process. The power converter is measured in both experiment and simulation in terms of frequency and electrical characteristics.Findings – Experimental results show that the converter with the stacked spiral inductor operates properly with the inductance of 7.6 nH and mW power range. The measured inductance of the stacked spiral inductor is found to be almost half of the circuit designed value because of the parasitic resistances and capacitances in the spiral inductor.Originality/value – This paper first introduces the application of the integrated stacked spiral inductor in DC‐DC buck...

Integrated Current-Mode DC-DC Buck Converter with Low-Power Control Circuit

A low power CMOS control circuit is applied in an integrated DC-DC buck converter. The integrated converter is composed of a feedback control circuit and power block with 0.35 μm CMOS process. A current-sensing circuit is integrated with the sense-FET method in the control circuit. In the current-sensing circuit, a current-mirror is used for a voltage follower in order to reduce power consumption with a smaller chip-size. The N-channel MOS acts as a switching device in the current-sensing circuit where the sensing FET is in parallel with the power MOSFET. The amplifier and comparator are designed to obtain a high gain and a fast transient time. The converter offers well- controlled output and accurately sensed inductor current. Simulation work shows that the current-sensing circuit is operated with an accuracy of higher than 90% and the transient time of the error amplifier is controlled within 75 μsec. The sensing current is in the range of a few hundred μA at a frequency of 0.6~2 MHz and an input voltage of 3~5 V. The output voltage is obtained as expected with the ripple ratio within 1%.

Integrated 0.35 µm BiCMOS DC-DC Boost Converter

The simulation and experimental study of current-mode DC-DC boost converter is presented in this paper The DC-DC converter is designed with a standard 0.35µm BiCMOS process. The off-chip LC filter is operated with the inductance of 1mH and capacitance of 100µF. The simulation results show the high performance DC-DC boost converter. The output voltage from simulation is obtained to be 5.8V with ripple ratio of 1.5%. The result corresponds with the experimental result within 5% error. The sensing current is obtained to be within 1mA and follows to fit the order of the aspect ratio between sensing and power MOSFET.

Basic fibroblast growth factor-induced translocation of p21-activated kinase to the membrane is independent of phospholipase C-γ1 in the differentiation of PC12 cells

p21-activated kinase (PAK) targeting to the plasma membrane is essential for PC12 cell neurite outgrowth. Phospholipase C-γ1 (PLC-γ1) can mediate the PAK translocation in response to growth factors, since PLC-γ1 binds to both tyrosine-phosphorylated receptor tyrosine kinases and PAK through its SH2 and SH3 domain, respectively. In the present study, we examined a potential role for PLC-γ1 in the basic fibroblast growth factor (bFGF)-induced PAK translocation using stable PC12 cell lines that overexpress in a tetracycline-inducible manner either the wild-type FGFR-1 or the Y766F FGFR-1 mutant. Phosphatidylinositol hydrolysis was increased 6.5-fold in response to bFGF in the wild type cells but negligible in the mutant cells. The recombinant GST-PLC-γ1 SH3 was able to bind to PAK1 but not GST alone. However, examination of PLC-γ1 as an adaptor for translocation of PAK1 in cells showed that both cells transfected with pEGFP-PAK1 was able to differentiate for 24 h, as visualized by laser confocal microscopy. Translocation of PAK1 to growth cones occurs at similar levels in both wild and mutant cells. These results suggest that a protein(s) other than PLC-γ1 is functionally relevant for PAK targeting.