biomembrane-fabrication-solvent-assisted-lipid-bilayer-salb

Biomembrane Fabrication by the Solvent-assisted Lipid Bilayer (SALB) Method

In order to mimic cell membranes, the supported lipid bilayer (SLB) is an attractive platform which enables in vitro investigation of membrane-related ...

Nanyang Technological University

Respiratory distress syndrome (RDS), which is induced by insufficient production of surfactant, is the leading cause of mortality in preterm babies. Although several transcription factors are known to be involved in surfactant protein expression, the molecular mechanisms and signaling pathways upstream of these transcription factors have remained elusive. Here, using mammalian Hippo kinases (Mst1/2, mammalian sterile 20-like kinase 1/2) conditional knockout mice, we demonstrate that Mst1/2 kinases are critical for orchestration of transcription factors involved in surfactant protein homeostasis and prevention of RDS. Mice lacking Mst1/2 in the respiratory epithelium exhibited perinatal mortality with respiratory failure and their lungs contained fewer type I pneumocytes and more immature type II pneumocytes lacking microvilli, lamellar bodies, and surfactant protein expression, pointing to peripheral lung immaturity and RDS. In contrast to previous findings of YAP (Yes-associated protein)-mediated canonical Hippo signaling in the liver and intestine, loss of Mst1/2 kinases induced the defects in pneumocyte differentiation independently of YAP hyperactivity. We instead found that Mst1/2 kinases stabilized and phosphorylated the transcription factor Foxa2 (forkhead box A2), which regulates pneumocyte maturation and surfactant protein expression. Taken together, our results suggest that the mammalian Hippo kinases play crucial roles in surfactant homeostasis and coordination of peripheral lung differentiation through regulation of Foxa2 rather than of YAP.

Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis.

Actin cytoskeletal damage induces inactivation of the oncoprotein YAP (Yes-associated protein). It is known that the serine/threonine kinase LATS (large tumour suppressor) inactivates YAP by phosphorylating its Ser127 and Ser381 residues. However, the events downstream of actin cytoskeletal changes that are involved in the regulation of the LATS-YAP pathway and the mechanism by which LATS differentially phosphorylates YAP on Ser127 and Ser381 in vivo have remained elusive. Here, we show that cyclic AMP (cAMP)-dependent protein kinase (PKA) phosphorylates LATS and thereby enhances its activity sufficiently to phosphorylate YAP on Ser381. We also found that PKA activity is involved in all contexts previously reported to trigger the LATS-YAP pathway, including actin cytoskeletal damage, G-protein-coupled receptor activation, and engagement of the Hippo pathway. Inhibition of PKA and overexpression of YAP cooperate to transform normal cells and amplify neural progenitor pools in developing chick embryos. We also implicate neurofibromin 2 as an AKAP (A-kinase-anchoring protein) scaffold protein that facilitates the function of the cAMP/PKA-LATS-YAP pathway. Our study thus incorporates PKA as novel component of the Hippo pathway.

cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes.

Primary cilia are microtubule-based organelles that protrude from polarized epithelial cells. Although many structural and trafficking molecules that regulate ciliogenesis have been discovered, signalling proteins are not well defined. Here we show that the MST1/2-SAV1 complex, a core component of the Hippo pathway, promotes ciliogenesis. MST1 is activated during ciliogenesis and localizes to the basal body of cilia. Depletion of MST1/2 or SAV1 impairs ciliogenesis in cultured cells and induces ciliopathy phenotypes in zebrafish. MST1/2-SAV1 regulates ciliogenesis through two independent mechanisms: MST1/2 binds and phosphorylates Aurora kinase A (AURKA), leading to dissociation of the AURKA/HDAC6 cilia-disassembly complex; and MST1/2-SAV1 associates with the NPHP transition-zone complex, promoting ciliary localization of multiple ciliary cargoes. Our results suggest that components of the Hippo pathway contribute to establish a polarized cell structure in addition to regulating proliferation.

The MST1/2-SAV1 complex of the Hippo pathway promotes ciliogenesis.

Anomalous origin of one pulmonary artery from the ascending aorta (AOPA) is a rare congenital malformation. Fewer than 150 cases have been reported to date in the world, with 95 % of these documented during the first year of the patient's life. We encountered a rare case of AOPA associated with patent ductus arteriosus in a 41-year-old female, who had reached the most advanced age of any known, previously untreated AOPA patient. We herein present our findings for this patient on plain chest radiography, computed tomography, and perfusion scan.

Anomalous origin of the right pulmonary artery from the ascending aorta associated with patent ductus arteriosus: focusing on computed tomography findings.

Glomangiomatosis, a rare category of glomus tumors, comprises 2% to 3% of glomus tumors in adults. We report a case of glomangiomatosis in a 48-year-old man who underwent multiple excisions of recurrent soft tissue masses in the ankle and foot. Ultrasonography revealed multiple nodular soft tissue tumors and dilated vascular channels with increased blood flow, suggesting the presence of vascular tumors. Here, we discuss the ultrasonography imaging features of glomangiomatosis, which have not been previously reported, correlate them with magnetic resonance imaging findings, and provide a brief review of the literature.

A Case of Glomangiomatosis of the Ankle and Foot: Ultrasonographic Appearance Correlated With the Magnetic Resonance Imaging Findings.

YAP (yes-associated protein) and TAZ are oncogenic transcriptional co-activators downstream of the Hippo tumor-suppressor pathway. However, whether YAP and/or TAZ (YAP/TAZ) engage in transcriptional co-repression remains relatively unexplored. Here, we directly demonstrated that YAP/TAZ represses numerous target genes, including tumor-suppressor genes such as DDIT4 (DNA-damage-inducible transcript 4) and Trail (TNF-related apoptosis-inducing ligand). Mechanistically, the repressor function of YAP/TAZ requires TEAD (TEA domain) transcription factors. A YAP/TAZ-TEAD complex recruits the NuRD complex to deacetylate histones and alters nucleosome occupancy at target genes. Functionally, repression of DDIT4 and Trail by YAP/TAZ is required for mTORC1 (mechanistic target of rapamycin complex 1) activation and cell survival, respectively. Our demonstration of the transcriptional co-repressor activity of YAP/TAZ opens a new avenue for understanding the Hippo signaling pathway.

Transcriptional co-repressor function of the hippo pathway transducers YAP and TAZ.

The U.S. policy goals regarding influenza vaccination coverage rate among the elderly include the increase in the coverage rate and the elimination of disparities across racial/ethnic groups.

Cost-Effectiveness Analysis of a Television Campaign to Promote Seasonal Influenza Vaccination Among the Elderly.

Despite telemedicine's potential to improve patients' health outcomes and reduce costs in the ICU, hospitals have been slow to introduce telemedicine in the ICU due to high up-front costs and mixed evidence on effectiveness. This study's first aim was to conduct a cost-effectiveness analysis to estimate the incremental cost-effectiveness ratio of telemedicine in the ICU, compared with ICU without telemedicine, from the healthcare system perspective. The second aim was to examine potential cost saving of telemedicine in the ICU through probabilistic analyses and break-even analyses.

Economic Evaluation of Telemedicine for Patients in ICUs.

LATS1/2 (large tumor suppressor) kinases and the Angiomotin family proteins are potent inhibitors of the YAP (yes-associated protein) oncoprotein, but the underlying molecular mechanism is not fully understood. Here, we report for the first time that USP9X is a deubiquitinase of Angiomotin-like 2 (AMOTL2) and that AMOTL2 mono-ubiquitination is required for YAP inhibition. USP9X knockdown increased the LATS-mediated phosphorylation of YAP and decreased the transcriptional output of YAP. Conversely, over-expression of USP9X reactivated YAP in densely cultured cells. Both genetic and biochemical approaches identified AMOTL2 as a target of USP9X. AMOTL2 was found to be ubiquitinated at K347 and K408, which both reside in the protein's coiled-coil domain. The AMOTL2 K347/408R mutant, which cannot be ubiquitinated, was impaired in its ability to inhibit YAP. Furthermore, ubiquitinated AMOTL2 can bind to the UBA domain of LATS kinase, and this domain is required for the function of LATS. Our results provide novel insights into the activation mechanisms of core Hippo pathway components.

Article	Year
Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 23620511	2013
cAMP/PKA signalling reinforces the LATS-YAP pathway to fully suppress YAP in response to actin cytoskeletal changes. The EMBO journal\| PubMed ID: 23644383	2013
The MST1/2-SAV1 complex of the Hippo pathway promotes ciliogenesis. Nature communications\| PubMed ID: 25367221	2014
Anomalous origin of the right pulmonary artery from the ascending aorta associated with patent ductus arteriosus: focusing on computed tomography findings. Japanese journal of radiology\| PubMed ID: 25632853	2015
A Case of Glomangiomatosis of the Ankle and Foot: Ultrasonographic Appearance Correlated With the Magnetic Resonance Imaging Findings. Ultrasound quarterly\| PubMed ID: 25831152	2015
Transcriptional co-repressor function of the hippo pathway transducers YAP and TAZ. Cell reports\| PubMed ID: 25843714	2015
Cost-Effectiveness Analysis of a Television Campaign to Promote Seasonal Influenza Vaccination Among the Elderly. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research\| PubMed ID: 26297090	2015
Economic Evaluation of Telemedicine for Patients in ICUs. Critical care medicine\| PubMed ID: 26540398	2015
Role of Angiomotin-like 2 mono-ubiquitination on YAP inhibition. EMBO reports\| PubMed ID: 26598551	2015

Minchul Kim

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