A5054079816- Cellular transport and secretion
- Protein Kinase Regulation and GTPase Signaling
- PI3K/AKT/mTOR signaling in cancer
- Pancreatic function and diabetes
- Calcium signaling and nucleotide metabolism
- Metabolism, Diabetes, and Cancer
- Endoplasmic Reticulum Stress and Disease
- Cytokine Signaling Pathways and Interactions
- Trypanosoma species research and implications
- Erythrocyte Function and Pathophysiology
- Microtubule and mitosis dynamics
- Mast cells and histamine
- Biochemical and Molecular Research
- Protein Degradation and Inhibitors
- Cancer-related Molecular Pathways
- Chronic Lymphocytic Leukemia Research
- Vibrio bacteria research studies
- Estrogen and related hormone effects
- Cancer, Hypoxia, and Metabolism
- Autophagy in Disease and Therapy
- Cell death mechanisms and regulation
- Cancer Mechanisms and Therapy
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Sirtuins and Resveratrol in Medicine
- NF-κB Signaling Pathways
Vanderbilt University Medical Center
2023-2024
University of South Alabama
2024
Vanderbilt University
2020-2022
Boston University
2013-2020
Boston Biomedical Research Institute
2002-2014
Beth Israel Deaconess Medical Center
1998-2014
Cornell University
2014
Agios Pharmaceuticals (United States)
2014
Scripps Research Institute
2014
Dana-Farber Cancer Institute
1997-2014
Phagosomes acquire their microbicidal properties by fusion with lysosomes. Products of phosphatidylinositol 3-kinase (PI 3-kinase) are required for phagosome formation, but role in maturation is unknown. Using chimeric fluorescent proteins encoding tandem FYVE domains, we found that 3-phosphate (PI[3]P) accumulates greatly transiently on the phagosomal membrane. Unlike 3′-phosphoinositides generated class I PI 3-kinases which evident nascent cup, PI(3)P only detectable after has sealed. The...
Pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains are structurally related regulatory modules that present in a variety of proteins involved signal transduction, such as kinases, phospholipases, GTP exchange proteins, adapter proteins. Initially these were shown to mediate protein-protein interactions, but more recently they also found bind phosphoinositides. Most studies date have focused on PH phosphatidylinositol (PtdIns)-4-P PtdIns-4,5-P<sub>2</sub> not considered the...
A microRNA network regulates the tumor suppressor PTEN in prostate cancer.
Both the anabolic hormone insulin and contractile activity stimulate uptake of glucose into mammalian skeletal muscle. In this study, we examined role phosphatidylinositol 3-kinase (PI 3-kinase), a putative mediator actions, in stimulation hexose response to contraction. Phosphatidylinositol 3,4-bisphosphate 3,4,5-triphosphate accumulate muscle exposed but not hypoxia, which mimics contractile-dependent pathway transport activation. The fungal metabolite wortmannin, an inhibitor PI 3-kinase,...
It has been demonstrated that the lipid products of phosphoinositide 3-kinase (PI3K) can associate with Src homology 2 (SH2) domains specific signaling molecules and modify their actions. In current experiments, phosphatidylinositol 3,4,5-trisphosphate (PtdIns-3,4,5-P<sub>3</sub>) was found to bind C-terminal SH2 domain phospholipase Cγ (PLCγ) an apparent <i>K</i> <sub>d</sub> 2.4 μm displace from activated platelet-derived growth factor receptor (PDGFR). To investigate <i>in...
Salmonella colonizes a vacuolar niche in host cells during infection. Maturation of the Salmonella-containing vacuole (SCV) involves formation phosphatidylinositol 3-phosphate (PI(3)P) on its outer leaflet. SopB, bacterial virulence factor with phosphoinositide phosphatase activity, was proposed to generate PI(3)P by dephosphorylating PI(3,4)P2, PI(3,5)P2, and PI(3,4,5)P3. Here, we examine mechanism SopB is required form PI(3,4)P2/PI(3,4,5)P3 at invasion ruffles nascent SCVs. However,...
Receptor tyrosine kinases limit their own activity by stimulating that promote trafficking of the receptors to lysosome.
Cellular levels of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P<sub>3</sub>) are rapidly elevated in response to activation growth factor receptor tyrosine kinases. This polyphosphoinositide binds the pleckstrin homology (PH) domain GRP1, a protein that also contains 200 residues with high sequence similarity segment yeast Sec7 functions as an ADP ribosylation exchange (ARF) (Klarlund, J., Guilherme, A., Holik, J. Virbasius, V., Chawla, and Czech, M. P. (1997)<i>Science</i> 275,...
We have investigated the functional role of SH2 domain 85-kDa subunit (p85) phosphatidylinositol 3-kinase in insulin signal transduction pathway. Microinjection a bacterial fusion protein containing N-terminal p85 inhibited insulin- and other growth factor-induced DNA synthesis by 90% c-fos expression 80% insulin-responsive rat fibroblasts. The specificity was examined vitro precipitation experiments, which showed that can independently associate with both receptor substrate 1 itself absence...
Phosphatidylinositol-5-phosphate (PI-5-P) is a newly identified phosphoinositide with characteristics of signaling lipid but no known cellular function. PI-5-P levels are controlled by the type II 4-kinases (PIP4K IIs), family kinases that converts into phosphatidylinositol-4,5-bisphosphate (PI-4,5-P 2 ). The pathway an alternative route for PI-4,5-P synthesis as bulk this generated canonical in which phosphatidylinositol-4-phosphate (PI-4-P) intermediate. Here we examined effect activation...
PtdIns5P was discovered in 1997 [Rameh, Tolias, Duckworth and Cantley (1997) Nature 390, 192-196], but still very little is known about its regulation function. Hitherto, studies of have been hindered by the inability to measure cellular using conventional HPLC, owing poor separation from PtdIns4P. In present paper we describe a new HPLC method for resolving PtdIns4P, which makes possible accurate measurements basal inducible levels context other phosphoinositides. Using this method, found...
Inositol phospholipids regulate a variety of cellular processes including proliferation, survival, vesicular trafficking, and cytoskeletal organization. Recently, two novel phosphoinositides, phosphatidylinositol-3,5-bisphosphate (PtdIns-3,5-P<sub>2</sub>) phosphatidylinositol- 5-phosphate (PtdIns-5-P), have been shown to exist in cells. PtdIns-3,5-P<sub>2</sub>, which is regulated by osmotic stress, appears be synthesized phosphorylation PtdIns-3-P at the D-5 position. No evidence yet...
Phosphorylated derivatives of the lipid phosphatidylinositol are known to play critical roles in insulin response. Phosphatidylinositol 5-phosphate 4-kinases convert 4,5-bis-phosphate. To understand physiological role these kinases, we generated mice that do not express 4-kinase beta. These hypersensitive and have reduced body weights compared wild-type littermates. While adult male lacking beta significantly less fat than littermates, female increased sensitivity presence normal adiposity....
Elucidation of the role PtdIns(4,5)P2 in epithelial function has been hampered by inability to selectively manipulate cellular content this phosphoinositide. Here we report that SigD, a phosphatase derived from Salmonella, can effectively hydrolyze PtdIns(4,5)P2, generating PtdIns(5)P. When expressed microinjecting cDNA into cells forming confluent monolayers, wild-type SigD induced striking morphological and functional changes were not mimicked phosphatase-deficient mutant (C462S)....