Understanding Ras Spatial Cycles Through Reaction-Diffusion Simulations.

Reaction-diffusion simulations allow us to recapitulate experimentally observed behavior, e.g., from time series of fluorescent micrographs.

A self-organized synthetic morphogenic liposome responds with shape changes to local light cues.

Reconstituting artificial proto-cells capable of transducing extracellular signals into cytoskeletal changes can reveal fundamental principles of how non-equilibrium phenomena in cellular signal transduction affect morphogenesis. Here, we generated a Synthetic Morphogenic Membrane System (SynMMS) by encapsulating a dynamic microtubule (MT) aster and a light-inducible signaling system driven by GTP/ATP chemical potential into cell-sized liposomes. Responding to light cues in analogy to morphogens, this biomimetic design embodies basic principles of localized Rho-GTPase signal transduction that generate an intracellular MT-regulator signaling gradient.

Spatial cycles mediated by UNC119 solubilisation maintain Src family kinases plasma membrane localisation.

The peripheral membrane proto-oncogene Src family protein tyrosine kinases relay growth factor signals to the cytoplasm of mammalian cells. We unravel the spatial cycles of solubilisation, trapping on perinuclear membrane compartments and vesicular transport that counter entropic equilibration to endomembranes for maintaining the enrichment and activity of Src family protein tyrosine kinases at the plasma membrane. The solubilising factor UNC119 sequesters myristoylated Src family protein tyrosine kinases from the cytoplasm, enhancing their diffusion to effectively release Src family protein tyrosine kinases on the recycling endosome by localised Arl2/3 activity.

EGF-dependent re-routing of vesicular recycling switches spontaneous phosphorylation suppression to EGFR signaling.

Autocatalytic activation of epidermal growth factor receptor (EGFR) coupled to dephosphorylating activity of protein tyrosine phosphatases (PTPs) ensures robust yet diverse responses to extracellular stimuli. The inevitable tradeoff of this plasticity is spontaneous receptor activation and spurious signaling. We show that a ligand-mediated switch in EGFR trafficking enables suppression of spontaneous activation while maintaining EGFR's capacity to transduce extracellular signals.

The Function of Embryonic Stem Cell-expressed RAS (E-RAS), a Unique RAS Family Member, Correlates with Its Additional Motifs and Its Structural Properties.

E-RAS is a member of the RAS family specifically expressed in embryonic stem cells, gastric tumors, and hepatic stellate cells. Unlike classical RAS isoforms (H-, N-, and K-RAS4B), E-RAS has, in addition to striking and remarkable sequence deviations, an extended 38-amino acid-long unique N-terminal region with still unknown functions. We investigated the molecular mechanism of E-RAS regulation and function with respect to its sequence and structural features.

Ras moves to stay in place.

Ras is a major intracellular signaling hub. This elevated position comes at a precarious cost: a single point mutation can cause aberrant signaling. The capacity of Ras for signaling is inextricably linked to its enrichment at the plasma membrane (PM).

KRas localizes to the plasma membrane by spatial cycles of solubilization, trapping and vesicular transport.

KRas is a major proto-oncogene product whose signaling activity depends on its level of enrichment on the plasma membrane (PM). This PM localization relies on posttranslational prenylation for membrane affinity, while PM specificity has been attributed to electrostatic interactions between negatively charged phospholipids in the PM and basic amino-acids in the C terminus of KRas. By measuring kinetic parameters of KRas dynamics in living cells with a cellular-automata-based data-fitting approach in realistic cell-geometries, we show that charge-based specificity is not sufficient to generate PM enrichment in light of the total surface area of endomembranes.

The interdependence of membrane shape and cellular signal processing.

Cellular membranes are constantly reshaped by vesicular fission and fusion as well as by interactions with the dynamic cytoskeleton. Signaling activity at membranes depends on their geometric parameters, such as surface area and curvature; these affect local concentration and thereby regulate the potency of molecular reactions. A membrane's shape is thus inextricably tied to information processing.

Signaling from the living plasma membrane.

Our understanding of the plasma membrane, once viewed simply as a static barrier, has been revolutionized to encompass a complex, dynamic organelle that integrates the cell with its extracellular environment. Here, we discuss how bidirectional signaling across the plasma membrane is achieved by striking a delicate balance between restriction and propagation of information over different scales of time and space and how underlying dynamic mechanisms give rise to rich, context-dependent signaling responses. In this Review, we show how computer simulations can generate counterintuitive predictions about the spatial organization of these complex processes.

Gaussian distributions of rotational velocities in a granular medium.

We investigate experimentally a homogeneously driven granular medium. It consists of spheres, each one containing a magnetic dipole, rolling on a horizontally placed dish and subject to a magnetic field which is sinusoidal in time and spatially homogeneous. A gaslike state is obtained.

Fluctuation theorem for a single particle in a moving billiard: experiments and simulations.

A single particle within a periodically driven Sinai-billiard-like system is tracked experimentally and is simulated via hard-sphere molecular dynamics. Both experiments and simulations confirm the fluctuation theorem (FT); thus, in this setup, one driven particle is sufficient for the FT to hold. Furthermore, in the simulations the chaoticity of the system can be adjusted using the restitution coefficient of collisions.

Experimental observations of oscillations and segregation in a binary granular mixture.

We present experimental evidence for a "granular clock." We use a setup in which vertical vibrations (10-20 Hz) of a bidisperse granular medium cause horizontal oscillations (periods in the order of minutes) between two connected compartments. Moreover, we present the first experimental evidence for full segregation of smaller particles into one compartment, leaving the larger ones in the other compartment.

Fluctuation theorem for a deterministic one-particle system.

A Duffing oscillator is driven by a sum of N chaotic time series. These time series are solutions of the undriven Duffing equation. It is shown that N=1 is sufficient to render the fluctuation theorem [Phys.

On-off intermittency and intermingledlike basins in a granular medium.

Molecular dynamic simulations of a medium consisting of disks in a periodically tilted box yield two dynamic modes differing considerably in the total potential and kinetic energies of the disks. Depending on parameters, these modes display the following features: (i) hysteresis (coexistence of the two modes in phase space); (ii) intermingledlike basins of attraction (uncertainty exponent indistinguishable from zero); (iii) two-state on-off intermittency; and (iv) bimodal velocity distributions. Bifurcations are defined by a cross-shaped phase diagram.