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https://www.readbyqxmd.com/read/29786068/mitochondrial-pip3-binding-protein-fundc2-supports-platelet-survival-via-akt-signaling-pathway
#1
Qi Ma, Chongzhuo Zhu, Weilin Zhang, Na Ta, Rong Zhang, Lei Liu, Du Feng, Heping Cheng, Junling Liu, Quan Chen
Platelets undergo apoptosis in response to a variety of stimuli in the circulation. Mitochondria in platelets are essential for their apoptosis. Specifically, pro-survival protein BCL-xL on mitochondria is the key regulator of platelet lifespan. Here we identify an outer mitochondrial membrane protein FUNDC2 for platelet survival. FUNDC2 knockout mice carrying excessively apoptotic platelets exhibit thrombocytopenia in response to hypoxia. Mechanistically, FUNDC2 binds the lipid PIP3 via its unique, highly conserved N-terminal motif...
May 21, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29780388/regulation-of-hematopoietic-cell-development-and-function-through-phosphoinositides
#2
REVIEW
Mila Elich, Karsten Sauer
One of the most paramount receptor-induced signal transduction mechanisms in hematopoietic cells is production of the lipid second messenger phosphatidylinositol(3,4,5)trisphosphate (PIP3 ) by class I phosphoinositide 3 kinases (PI3K). Defective PIP3 signaling impairs almost every aspect of hematopoiesis, including T cell development and function. Limiting PIP3 signaling is particularly important, because excessive PIP3 function in lymphocytes can transform them and cause blood cancers. Here, we review the key functions of PIP3 and related phosphoinositides in hematopoietic cells, with a special focus on those mechanisms dampening PIP3 production, turnover, or function...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29757152/dynamic-seesaw-model-for-rapid-signaling-responses-in-eukaryotic-chemotaxis
#3
Shiliang Feng, Lvwen Zhou, ShouQin Lü, Yan Zhang
Directed movement of eukaryotic cells toward spatiotemporally varied chemotactic stimuli enables rapid intracellular signaling responses. While macroscopic cellular manifestation is shaped by balancing external stimuli strength with finite internal delays, the organizing principles of the underlying molecular mechanisms remain to be clarified. Here, we developed a novel modeling framework based on a simple seesaw mechanism to elucidate how cells repeatedly reverse polarity. As a key feature of the modeling, the bottom module of bidirectional molecular transport is successively controlled by three upstream modules of signal reception, initial signal processing, and Rho GTPase regulation...
May 14, 2018: Physical Biology
https://www.readbyqxmd.com/read/29715315/a-pkc-marcks-pi3k-regulatory-module-links-ca2-and-pip3-signals-at-the-leading-edge-of-polarized-macrophages
#4
Brian P Ziemba, Joseph J Falke
The leukocyte chemosensory pathway detects attractant gradients and directs cell migration to sites of inflammation, infection, tissue damage, and carcinogenesis. Previous studies have revealed that local Ca2+ and PIP3 signals at the leading edge of polarized leukocytes play central roles in positive feedback loop essential to cell polarization and chemotaxis. These prior studies showed that stimulation of the leading edge Ca2+ signal can strongly activate PI3K, thereby triggering a larger PIP3 signal, but did not elucidate the mechanistic link between Ca2+ and PIP3 signaling...
2018: PloS One
https://www.readbyqxmd.com/read/29712722/melanopsin-opn4-employs-g%C3%AE-i-and-g%C3%AE-%C3%AE-as-major-signal-transducers
#5
Dinesh Kankanamge, Kasun Ratnayake, Saroopa Samaradivakara, Ajith Karunarathne
Melanopsin (Opn4), a ubiquitously expressed photoreceptor in all classes of vertebrates, is crucial for both visual and non-visual signaling. Opn4 supports visual functions of the eye by sensing radiance levels and discriminating contrast and brightness. Non-image forming (NIF) functions of Opn4 not only regulate circadian behavior, but also control growth and development processes of the retina. Nevertheless, it is unclear how a single photoreceptor governs such a diverse range of physiological functions. While genetic hardwiring of host cells is thought to be a source, molecular and mechanistic justifications for the prominent functional diversity of Opn4 are lacking...
April 30, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29706633/a-pathogenic-role-for-germline-pten-variants-which-accumulate-into-the-nucleus
#6
Janire Mingo, Isabel Rodríguez-Escudero, Sandra Luna, Teresa Fernández-Acero, Laura Amo, Amy R Jonasson, Roberto T Zori, José I López, María Molina, Víctor J Cid, Rafael Pulido
The PTEN gene encodes a master regulator protein that exerts essential functions both in the cytoplasm and in the nucleus. PTEN is mutated in the germline of both patients with heterogeneous tumor syndromic diseases, categorized as PTEN hamartoma tumor syndrome (PHTS), and a group affected with autism spectrum disorders (ASD). Previous studies have unveiled the functional heterogeneity of PTEN variants found in both patient cohorts, making functional studies necessary to provide mechanistic insights related to their pathogenicity...
April 30, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29681901/putting-on-the-brakes-regulatory-kinases-and-phosphatases-maintaining-b-cell-anergy
#7
REVIEW
S Elizabeth Franks, John C Cambier
B cell antigen receptor (BCR) signaling is a tightly regulated process governed by both positive and negative mediators/regulators to ensure appropriate responses to exogenous and autologous antigens. Upon naïve B cell recognition of antigen CD79 [the immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling subunit of the BCR] is phosphorylated and recruits Src and Syk family kinases that then phosphorylate proximal intermediaries linked to downstream activating signaling circuitry. This plasma membrane localized signalosome activates PI3K leading to generation of PIP3 critical for membrane localization and activation of plecktrin homology domain-containing effectors...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29616047/molecular-mechanisms-of-human-disease-mediated-by-oncogenic-and-primary-immunodeficiency-mutations-in-class-ia-phosphoinositide-3-kinases
#8
REVIEW
Gillian L Dornan, John E Burke
The signaling lipid phosphatidylinositol 3,4,5, trisphosphate (PIP3 ) is an essential mediator of many vital cellular processes, including growth, survival, and metabolism. PIP3 is generated through the action of the class I phosphoinositide 3-kinases (PI3K), and their activity is tightly controlled through interactions with regulatory proteins and activating stimuli. The class IA PI3Ks are composed of three distinct p110 catalytic subunits (p110α, p110β, and p110δ), and they play different roles in specific tissues due to disparities in both expression and engagement downstream of cell-surface receptors...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29563327/inhibition-of-the-%C3%AE-subunit-of-phosphoinositide-3-kinase-pi3k-in-heart-increases-late-sodium-current-and-is-arrhythmogenic
#9
Tao Yang, David F Meoli, Javid Moslehi, Dan M Roden
While inhibition of phosphoinositide 3-kinase (PI3K) is an emerging strategy in cancer therapy, we and others have reported that this action can also contribute to drug-induced Q-T prolongation and arrhythmias by increasing cardiac late sodium current (INaL). Previous studies in mice implicate the PI3K-α isoform as the major effector of the INaL action. Here, we have determined the effects of new anticancer drugs targeting specific PI3K isoforms on INaL and action potentials (APs) in mouse cardiomyocytes and CHO cells...
March 21, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29535262/skp2-dependent-reactivation-of-akt-drives-resistance-to-pi3k-inhibitors
#10
Emilie Clement, Hiroyuki Inuzuka, Naoe T Nihira, Wenyi Wei, Alex Toker
The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways...
March 13, 2018: Science Signaling
https://www.readbyqxmd.com/read/29530984/cytochrome-c-is-an-oxidative-stress-activated-plasmalogenase-that-cleaves-plasmenylcholine-and-plasmenylethanolamine-at-the-sn-1-vinyl-ether-linkage
#11
Christopher M Jenkins, Kui Yang, Gaoyuan Liu, Sung Ho Moon, Beverly G Dilthey, Richard W Gross
Plasmalogens are phospholipids critical for cell function and signaling that contain a vinyl-ether linkage at the   sn -1 position and are highly enriched in arachidonic acid (AA) at the sn -2 position. However, the enzyme(s) responsible for the cleavage of the vinyl ether linkage in plasmalogens has remained elusive.  Herein, we report that cytochrome c , in the presence of either cardiolipin (CL), O2 and H2 O2 , or oxidized CL and O2 , catalyzes the oxidation of the plasmalogen vinyl ether linkage, promoting its hydrolytic cleavage and resultant production of 2-AA-lysolipids and highly reactive α-hydroxy fatty aldehydes...
March 12, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29490947/metabolic-determinants-of-sensitivity-to-phosphatidylinositol-3-kinase-pathway-inhibitor-in-small-cell-lung-carcinoma
#12
Hideki Makinoshima, Shigeki Umemura, Ayako Suzuki, Hiroki Nakanishi, Ami Maruyama, Hibiki Udagawa, Sachiyo Mimaki, Shingo Matsumoto, Seiji Niho, Genichiro Ishii, Masahiro Tsuboi, Atsushi Ochiai, Hiroyasu Esumi, Takehiko Sasaki, Koichi Goto, Katsuya Tsuchihara
Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here, we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3 ) subspecies lipid product PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor...
May 1, 2018: Cancer Research
https://www.readbyqxmd.com/read/29483218/targeting-polo-like-kinase-1-by-a-novel-pyrrole-imidazole-polyamide-hoechst-conjugate-suppresses-tumor-growth-in-vivo
#13
Ke Liu, Lijing Fang, Haiyan Sun, Zhengyin Pan, Jianchao Zhang, Juntao Chen, Ximing Shao, Wei Wang, Yuanyan Tan, Zhihao Ding, Lijiao Ao, Chunlei Wu, Xiaoqi Liu, Huashun Li, Rui Wang, Wu Su, Hongchang Li
The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst conjugate, PIP3, targeted to specific DNA sequence in the PLK1 promoter...
May 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29470948/direct-analysis-of-pi-3-4-5-p-3-using-liquid-chromatography-electrospray-ionization-tandem-mass-spectrometry
#14
Hai H Bui, Phillip E Sanders, Diane Bodenmiller, Ming Shang Kuo, Gregory P Donoho, Anthony S Fischl
Phosphatidylinositol (3,4,5) trisphosphate (PIP3 ) is a biologically active membrane phospholipid that is essential for the growth and survival of all eukaryotic cells. We describe a new method that directly measures PIP3 and describe the HPLC separation and measurement of the positional isomers of phosphatidylinositol bisphosphate, PI(3,5)P2 , PI(3,4)P2 and PI(4,5)P2 . Mass spectrometric analyses were performed online using ultra-high performance liquid chromatography (UHPLC)-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) in the negative multiple-reaction monitoring (MRM) modes...
April 15, 2018: Analytical Biochemistry
https://www.readbyqxmd.com/read/29444849/amplification-of-pip3-signalling-by-macropinocytic-cups
#15
Robert R Kay, Thomas D Williams, Peggy Paschke
In a role distinct from and perhaps more ancient than that in signal transduction, PIP3 and Ras help to spatially organize the actin cytoskeleton into macropinocytic cups. These large endocytic structures are extended by actin polymerization from the cell surface and have at their core an intense patch of active Ras and PIP3, around which actin polymerizes, creating cup-shaped projections. We hypothesize that active Ras and PIP3 self-amplify within macropinocytic cups, in a way that depends on the structural integrity of the cup...
February 14, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29434596/insight-into-phosphatidylinositol-dependent-membrane-localization-of-the-innate-immune-adaptor-protein-toll-interleukin-1-receptor-domain-containing-adaptor-protein
#16
Mahesh Chandra Patra, Sangdun Choi
The toll/interleukin 1 receptor (TIR) domain-containing adaptor protein (TIRAP) plays an important role in the toll-like receptor (TLR) 2, TLR4, TLR7, and TLR9 signaling pathways. TIRAP anchors to phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) on the plasma membrane and PI (3,4,5)-trisphosphate (PIP3) on the endosomal membrane and assists in recruitment of the myeloid differentiation primary response 88 protein to activated TLRs. To date, the structure and mechanism of TIRAP's membrane association are only partially understood...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29420173/asymmetric-pi3k-activity-in-lymphocytes-organized-by-a-pi3k-mediated-polarity-pathway
#17
Yen-Hua Chen, Radomir Kratchmarov, Wen-Hsuan W Lin, Nyanza J Rothman, Bonnie Yen, William C Adams, Simone A Nish, Jeffrey C Rathmell, Steven L Reiner
Unequal transmission of nutritive signaling during cell division establishes fate disparity between sibling lymphocytes, but how asymmetric signaling becomes organized is not understood. We show that receptor-associated class I phosphatidylinositol 3-kinase (PI3K) signaling activity, indexed by phosphatidylinositol (3,4,5)-trisphosphate (PIP3 ) staining, is spatially restricted to the microtubule-organizing center and subsequently to one pole of the mitotic spindle in activated T and B lymphocytes. Asymmetric PI3K activity co-localizes with polarization of antigen receptor components implicated in class I PI3K signaling and with facultative glucose transporters whose trafficking is PI3K dependent and whose abundance marks cells destined for differentiation...
January 23, 2018: Cell Reports
https://www.readbyqxmd.com/read/29357370/parallel-pi3k-akt-and-mtor-inhibition-is-required-to-control-feedback-loops-that-limit-tumor-therapy
#18
Anuja Sathe, Géraldine Chalaud, Immanuel Oppolzer, Kit Yeng Wong, Margarita von Busch, Sebastian C Schmid, Zhichao Tong, Margitta Retz, Juergen E Gschwend, Wolfgang A Schulz, Roman Nawroth
Targeting the PI3K pathway has achieved limited success in cancer therapy. One reason for the disappointing activity of drugs that interfere with molecules that are important player in this pathway is the induction of multiple feedback loops that have been only partially understood. To understand these limitations and develop improved treatment strategies, we comprehensively characterized molecular mechanisms of PI3K pathway signaling in bladder cancer cell lines upon using small molecule inhibitors and RNAi technologies against all key molecules and protein complexes within the pathway and analyzed functional and molecular consequences...
2018: PloS One
https://www.readbyqxmd.com/read/29351408/choroid-plexus-epithelial-cells-express-the-adhesion-protein-p-cadherin-at-cell-cell-contacts-and-syntaxin-4-in-the-luminal-membrane-domain
#19
Inga Baasch Christensen, Esben Nees Mogensen, Helle Hasager Damkier, Jeppe Praetorius
The choroid plexus epithelial cells (CPECs) belong to a small group of polarized cells, where the Na+ ,K+ -ATPase is expressed in the luminal membrane. The basic polarity of the cells is, therefore, still debated. We investigated the subcellular distribution of an array of proteins known to play fundamental roles in either in establishing and maintaining basic cell polarity or the polarized delivery and recycling of plasma membrane proteins. Immunofluorescence histochemical analysis was applied to determine the subcellular localization of apical and basolateral membrane determinants...
January 10, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29288045/elevated-nuclear-phosphatase-and-tensin-homolog-pten-and-altered-insulin-signaling-in-substantia-nigral-region-of-patients-with-parkinson-s-disease
#20
Sathiya Sekar, Changiz Taghibiglou
Studies showed that 50-80% of Parkinson's disease (PD) patients have been reported with abnormal glucose tolerance. Alterations in glucose and energy metabolism serve as the early molecular event in PD. Although evidences support that the insulin resistance plays a major role in motor and non-motor complications of PD, the underlying mechanism in the pathogenesis of PD is unclear. To address this issue, we investigated the alterations in major components of insulin signaling in nuclear fraction (NF) and whole tissue homogenate (TH) of substantia nigral (SN) region obtained from postmortem PD brain and their age-matched controls...
February 14, 2018: Neuroscience Letters
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