An animation of protein dynamics was created by Cameron Slayden with the scientific oversight of Carole A. Parent and Alan R. Kimmel.
Animation 1. Spatial and temporal dynamics of signaling components involved in the control of chemotaxis in Dictyostelium discoideum.
Under quiescent (unstimulated) conditions, the cAMP receptors (cARs) are randomly distributed around the surface of the cell in tight association with heterotrimeric G protein subunits. The PTEN phosphatase, adenylyl cyclase A (ACA), and the kinase PAKa are preferentially localized at the plasma membrane (PM), whereas phosphoinositide 3-kinase (PI3K) and its immediate downstream effectors, the pleckstrin homology (PH) domain proteins, are primarily cytosolic. F-actin and myosin II accumulate at the cortex--the inner membrane perimeter.
In the presence of a global, uniform extracellular cAMP stimulus, there is a rapid and dramatic redistribution of signaling components. Upon stimulation of the cARs, the G proteins become activated leading to a dissociation of Ga-GTP and Gbg subunits. PTEN is delocalized to the cytosol, whereas PI3K becomes preferentially associated with the PM; this yields a consequent net accumulation of PI(3,4,5)P3 at the PM that recruits the PH proteins. [Note: In the presence of an unvarying, global cAMP stimulus (not shown), the cells become adapted and the subcellular localizations of PTEN, PI3K, and the PH proteins revert to their pre-stimulated positions].
When placed in a cAMP gradient, the cells become highly polarized and chemotax in the direction of the gradient source. Under these conditions, the receptors and G proteins remain uniformly distributed. PI3K and PTEN, however, are reciprocally localized. PI3K accumulates at the leading edge, whereas PTEN is primarily found at the sides and rear. Collectively, this serves to limit PI(3,4,5)P3 and PH protein localizations to the leading edge. F-actin and myosin II largely follow this dichotomy. The polymerization of F-actin at the leading edge drives anterior protrusion in the direction of the chemoattractant gradient, whereas myosin II manifests cortical tension to suppress lateral pseudopod formation and to promote retraction of the rear in the direction of the gradient. Both ACA and PAKa, downstream effectors of specific PH proteins, localize preferentially to the rear of migrating cells.
Citation for the animation
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Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882