Four-dimensional organization of protein kinase signaling cascades: the roles of diffusion, endocytosis and molecular motors

Abstract

SUMMARYExtracellular signals received by membrane receptors are processed, encoded and transferred to the nucleus via phosphorylation and spatial relocation of protein members of multiple component pathways, such as mitogen activated protein kinase (MAPK) cascades. The receptor-induced membrane recruitment of the cytoplasmic protein SOS results in the activation of the Ras/MAPK cascade. It has been suggested that the membrane recruitment of signaling proteins causes an increase in the diffusion-limited rates. We have recently shown that this increase is too small to be responsible for enhanced signal transduction. Instead we demonstrate that the function of membrane localization is to increase the number (or average lifetime) of complexes between signaling partners. A hallmark of signaling pathways is the spatial separation of activation and deactivation mechanisms; e.g. a protein can be phosphorylated at the cell surface by a membrane-bound kinase and dephosphorylated in the cytosol by a cytosolic phosphatase. Given the measured values of protein diffusion coefficients and of phosphatase and kinase activities, the spatial separation is shown to result in precipitous phospho-protein gradients. When information transfer is hampered by slow protein diffusion and rapid dephosphorylation, phospho-protein trafficking within endocytic vesicles may be an efficient way to deliver messages to physiologically relevant locations. The proposed mechanism explains recent observations that various inhibitors of endocytosis can inhibit MAPK activation. Additional mechanisms facilitating the relay of signals from cell-surface receptors to the nucleus can involve the assembly of protein kinases on a scaffolding protein and active transport of signaling complexes by molecular motors. We also discuss long-range signaling within a cell, such as survival signaling in neurons. We hypothesize that ligand-independent waves of receptor activation or/and traveling waves of phosphorylated kinases emerge to spread the signals over long distances.

Signaling cascades as cellular devices for spatial computations

“…This termination of signaling by phosphatases necessitates mechanisms to facilitate signal propagation across a cell. In fact, recent experimental and theoretical work showed that endocytosis, scaffolding, molecular motors, and traveling waves of phospho-proteins are involved in the propagation of signals to different cellular locations [32][33][34].…”

“…Hence, although this scheme is more complicated than the systems discussed so far, it contains many regulatory interactions of the former. This is reflected in the model structure with respect to the rate laws for GTP hydrolysis and GDP→GTP exchange, respectively: (32) Note that for the 3 rd -level GEF we include constitutive activity and activation by the first GTPase.…”

Neuronal Calcium Sensor-1 and Phosphatidylinositol 4-Kinase β Stimulate Extracellular Signal-regulated Kinase 1/2 Signaling by Accelerating Recycling through the Endocytic Recycling Compartment

“…Although active ERK1/2 translocate to the nucleus (Volmat and Pouyssegur, 2001), mathematical calculations based on diffusion coefficients have anticipated that the rate of nuclear import of the activated ERKs could not be simply explained by diffusion of the cytosolic kinases (Kholodenko, 2003). Association with and movement along the endocytic pathway have therefore been suggested as a reasonable solution for the spatial segregation of the activated ERKs and facilitation of their transport toward the nucleus.…”

The topology design principles that determine the spatiotemporal dynamics of G-protein cascades

“…Since traveling waves propagate with a constant speed, the time of the signal transfer increases linearly with the cell size, whereas the time of signal propagation by diffusion is proportional to the square of the cell size. This is a reason why travelling waves can effectively transfer protein modification signals 47 .…”

“…Signaling pathways are spatially organized in living cells. Often, an activating enzyme and opposing deactivating enzyme are localized to distinct cellular structures 26,47 . For instance, activating signals can occur on the plasma membrane or intracellular membranes where receptors and effector-enzymes reside, while deactivating processes can be spread in the cytoplasm.…”