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Rab GTPases in Endocytosis Pathway definition: The eukaryotic cell contains compartments with distinct functions bounded by lipid bilayer membranes. The movement of membrane vesicles between these compartments allows proteins in the secretory pathway to move outward from the endoplasmic reticulum (ER) to the Golgi, trans Golgi network (TGN), secretory vesicles, and the plasma membrane and to be secreted into the extracellular environment. The trafficking of membrane vesicles is also essential for endocytosis and the movement of material from the extracellular environment into the early endosome (EE), late endosome (LE), and lysosome. The movement of vesicles and their contents between these compartments, and their secretion, are essential for a host of cellular functions, including the release of neurotransmitters and hormones. The movement of membrane vesicles between all of these compartments is regulated by members of the Rab family of GTPases, part of the ras superfamily of genes, regulated through binding of GTP and hydrolysis of bound GTP to GDP. At least eleven yeast genes in this family have been identified as Ypts, yeast transport proteins, and over sixty mammalian Rab genes have been identified in this highly conserved gene family. The products of the Rab genes regulate specific steps in vesicle transport. Rab1 is involved in the movement of membranes from the ER through the Golgi. Rab3 regulates secretory vesicle release and Rab27 is also involved in regulated release of secreted proteins. Rab5, 7 and 9 contribute to endocytosis while Rab4 and Rab11 mediate recycling from the endosome back to the plasma membrane. Rab11 is involved in both endocytosis and exocytosis. As with other Ras family GTPases, the activity of Rabs is regulated by guanine-nucleotide exchange factors (GEFs) and GAPs (GTPase activating proteins). Downstream effectors must also interact with Rabs to transmit their signals regulating each step of the membrane trafficking pathways including vesicle formation, movement of vesicles between compartments, vesicle docking, fusion, and membrane remodeling. Downstream effectors of the Rabs include Rabphilin-3 (vesicle movement effector for Rab3), Rabphilin-11 (vesicle formation effector for Rab11), and EEA1 (vesicle fusion and membrane remodeling). If Rabs are involved in more than one role and other components of Rab signaling also interact with more than one Rab this will further increase the complexity of the system. Elucidating the interaction of Rabs and regulation of vesicle trafficking by other signaling pathways will be a key area of research in the future. (BioCarta)
Extraordinary Opportunity: Molecular Targets of Prevention and Treatment definition: Goal: we now have very focused targets against which to direct prevention and therapy efforts. The Molecular Targets Initiative will seek to discover and develop novel prevention, therapeutic, diagnostic, and imaging agents based on our understanding of these targets. (NCI Web)
Extraordinary Opportunity: Molecular Targets of Prevention and Treatment definition: From NCI Priority Web page: Identifying molecular differences between normal cells and cancer cells will enable us to develop a whole new generation of treatments and preventives that affect only cancer cells.
Phosphoinositide Pathway definition: Nine currently identified phosphoinositide 3-kinases (PI 3-K) constitute a subfamily of lipid kinases that catalyze the addition of a phosphate molecule on the 3-position of the inositol ring of phosphoinositides. Phosphatidylinositol (PtdIns), the precursor of all phosphoinositides (PI), constitutes less than 10% of the total lipid in eukaryotic cell membranes. Approximately 5% of cellular PI is phosphorylated at the 4-position (PtdIns-4-P), and another 5% is phosphorylated at both the 4- and 5-positions (PtdIns-4, 5-P2). However, less than 0.25% of the total inositol-containing lipids are phosphorylated at the 3-position, consistent with the idea that these lipids exert specific regulatory functions inside the cell, as opposed to a structural function. Here we have chosen to highlight a group of the phosphoinositide targets of the PI3-Ks and their downstream targets. The downstream effects of these PI-3 targets are indicated, illustrating the important role the PI3Ks have in cell function and survival. (BioCarta)
GISTIC definition: A statistical approach for identifying genomic regions of aberration that are more likely to drive cancer pathogenesis. The method identifies those regions of the genome that are aberrant more often than would be expected by chance, with greater weight given to high-amplitude events (high-level copy-number gains or homozygous deletions) that are less likely to represent random aberrations.

Identifying transcriptional targets

Nicola V Taverner et al.

Genome Biology , 2004

Predicting and validating microRNA targets

Eric C Lai

Genome Biology , 2004

Identification of Drosophila MicroRNA Targets

Alexander Stark et al.

PLoS Biology , 01 Dec 2003

Human MicroRNA Targets

Bino John et al.

PLoS Biology , 01 Nov 2004

Therapeutic targets in systemic sclerosis

Christopher P Denton

Arthritis Research & Therapy , 2007

Apoptosis: Targets in Pancreatic Cancer

Sabine Westphal et al.

Molecular Cancer , 07 Jan 2003

Identification of Synaptic Targets of Drosophila Pumilio

Gengxin Chen et al.

PLoS Computational Biology , 01 Feb 2008

Quantitative analysis on the characteristics of targets with FDA approved drugs

Meena K. Sakharkar et al.

International Journal of Biological Sciences , 10 Dec 2007

Insect Detection of Small Targets Moving in Visual Clutter

Karin Nordström et al.

PLoS Biology , 01 Mar 2006

Synaptosomal Toxicity and Nucleophilic Targets of 4-Hydroxy-2-Nonenal

Richard M. LoPachin et al.

Toxicological Sciences , 01 Jan 2009

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