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

Boris N Kholodenko^*

Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA

View larger version (29K): [in a new window]   Fig.1. Signaling through the ERK (MAPK) cascade following activation of receptor tyrosine kinases (RTKs) and G-protein coupled receptors (GPCRs). RTKs activate the ERK cascade by recruiting guanine exchange factor SOS to the plasma membrane in close proximity to the membrane-anchored Ras. The upper right corner of the figure details the signaling activation route near the membrane surface. Below, it is shown that some of the signal transduction complexes, e.g. the Shc-Grb2-SOS and Grb2-SOS complexes, reside in the cytosol, raising the question of whether Ras activation occurs through direct interactions of SOS from the cytosol. Activated Ras-GTP promotes the activation of Raf-1, which phosphorylates MEK, which in turn activates ERK. Left, GPCRs stimulate MAPK cascades either through transactivation of RTKs, such as EGFR, or directly by using ß-arrestin as a scaffold for the ERK and JNK cascades. For abbreviations, see list. See text for further details.

View larger version (42K): [in a new window]   Fig.2. Decline in the phospho-protein concentration with distance from the cell membrane at different values of the parameter . The parameter is determined by the ratio of the characteristic times of diffusion and the phosphatase reaction (2=KpxL2/D, where L is the cell radius, Kp=Vmax,p/Km,p is the observed first-order rate constant of the phosphatase and D is the protein diffusion coefficient). The decline, p(x)/p(1), is calculated as the ratio of the concentrations of the phosphorylated form at distance xL from the cell center and at the plasma membrane, where x=1. Reproduced with permission from Kholodenko (2002).