title: Intracellular electric field and pH optimize protein localization and movement.
abstract: Mammalian cell function requires timely and accurate transmission of information from the cell membrane (CM) to the nucleus (N). These pathways have been intensively investigated and many critical components and interactions have been identified. However, the physical forces that control movement of these proteins have received scant attention. Thus, transduction pathways are typically presented schematically with little regard to spatial constraints that might affect the underlying dynamics necessary for protein-protein interactions and molecular movement from the CM to the N. We propose messenger protein localization and movements are highly regulated and governed by Coulomb interactions between: 1. A recently discovered, radially directed E-field from the NM into the CM and 2. Net protein charge determined by its isoelectric point, phosphorylation state, and the cytosolic pH. These interactions, which are widely applied in elecrophoresis, provide a previously unknown mechanism for localization of messenger proteins within the cytoplasm as well as rapid shuttling between the CM and N. Here we show these dynamics optimize the speed, accuracy and efficiency of transduction pathways even allowing measurement of the location and timing of ligand binding at the CM--previously unknown components of intracellular information flow that are, nevertheless, likely necessary for detecting spatial gradients and temporal fluctuations in ligand concentrations within the environment. The model has been applied to the RAF-MEK-ERK pathway and scaffolding protein KSR1 using computer simulations and in-vitro experiments. The computer simulations predicted distinct distributions of phosphorylated and unphosphorylated components of this transduction pathway which were experimentally confirmed in normal breast epithelial cells (HMEC).
authors.affiliation: Department of Radiology, Moffitt Cancer Center, Tampa, Florida, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cunningham
authors.forename: Veronica
authors.initials: V
authors.lastname: Estrella
authors.forename: Mark
authors.initials: M
authors.lastname: Lloyd
authors.forename: Robert
authors.initials: R
authors.lastname: Gillies
authors.forename: B Roy
authors.initials: BR
authors.lastname: Frieden
authors.forename: Robert
authors.initials: R
authors.lastname: Gatenby
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D003198:Computer Simulation; D004574:Electromagnetic Fields; D007526:Isoelectric Point; D008322:Mammals; D008954:Models, Biological; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011506:Proteins