Integration of Signaling Networks that Regulate <i>Dictyostelium</i> Differentiation

Aubry, Laurence; Firtel, Richard A.

doi:10.1146/annurev.cellbio.15.1.469

Cited by 151 publications

(104 citation statements)

References 245 publications

(218 reference statements)

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“…When cAR1 occupancy decreases in the back of the wave, both ERK2 and ACA are deactivated, resulting in an increase in RegA activity, a decrease in the internal concentration of cAMP, and a decrease in PKA activity. PKA also inhibits ERK2 (4,5), noted by a dashed line. Hence, when PKA activity increases, it begins to shut down ERK2 activity, resulting in an increase in RegA activity and a decrease in the intracellular cAMP concentration.…”

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confidence: 97%

“…CELL synthesis, and ERK2 inhibits the internal phosphodiesterase RegA (7,22,23,34). As the internal concentration of cAMP rises, PKA is activated, which inhibits ERK2 (4,5). When no longer inhibited by ERK2, RegA reduces the internal level of cAMP, which in turn leads to a reduction in PKA activity.…”

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confidence: 99%

“…Model of the regulatory circuitry for PKA activation during normal Dictyostelium chemotaxis. When the cAMP receptor cAR1 is occupied in the increasing phase of the wave, the mitogen-activated protein kinase ERK2 and ACA are activated (4,5,15,19). ERK2 inhibits the internal phosphodiesterase RegA (7,22,23,34), which allows cAMP, synthesized by ACA, to accumulate.…”

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Constitutively Active Protein Kinase A Disrupts Motility and Chemotaxis inDictyostelium discoideum

et al. 2003

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The deletion of the gene for the regulatory subunit of protein kinase A (PKA) results in constitutively active PKA in the pkaR mutant. To investigate the role of PKA in the basic motile behavior and chemotaxis of Dictyostelium discoideum, pkaR mutant cells were subjected to computer-assisted two-and three-dimensional motion analysis. pkaR mutant cells crawled at only half the speed of wild-type cells in buffer, chemotaxed in spatial gradients of cyclic AMP (cAMP) but with reduced efficiency, were incapable of suppressing lateral pseudopods in the front of temporal waves of cAMP, a requirement for natural chemotaxis, did not exhibit the normal velocity surge in response to the front of a wave, and were incapable of chemotaxing toward an aggregation center in natural waves generated by wild-type cells that made up the majority of cells in mixed cultures. Many of the behavioral defects appeared to be the result of the constitutively ovoid shape of the pkaR mutant cells, which forced the dominant pseudopod off the substratum and to the top of the cell body. The behavioral abnormalities that pkaR mutant cells shared with regA mutant cells are discussed by considering the pathway ERK2 OԽ RegA OԽ [cAMP] 3 PKA, which emanates from the front of a wave. The results demonstrate that cells must suppress PKA activity in order to elongate along a substratum, suppress lateralpseudopod formation, and crawl and chemotax efficiently. The results also implicate PKA activation in dismantling cell polarity at the peak and in the back of a natural cAMP wave.As a population of Dictyostelium amoebae aggregate to a center, each amoeba must respond to the different phases of relayed, outwardly moving, nondissipating symmetric waves of the chemoattractant cyclic AMP (cAMP) (Fig. 1). In the front of each wave, cells experience a positive spatial gradient of cAMP (i.e., the concentration increases in the direction of the aggregation center) and an increasing temporal gradient of cAMP (i.e., the concentration increases with time). At the peak of each wave, cells experience a cAMP concentration that causes cellular depolarization, and in the back of each wave, cells experience a negative spatial gradient of cAMP (i.e., the concentration decreases in the direction of the aggregation center) and a decreasing temporal gradient of cAMP (i.e., the concentration decreases with time) (Fig. 1). Amoebae respond to each phase of a natural wave in a distinct and reproducible fashion, resulting in a sequence of behaviors that together represent the natural chemotactic response (29,32,37,40,41,47,48). In the absence of any external chemotactic signal, Dictyostelium amoebae translocate at near-maximum velocity and turn frequently (47,48). We propose that this basic motile behavior is modulated in the different phases of the natural wave, with the net result of directing cells into the aggregation center (29) (Fig. 1). During aggregation, cells are exposed to a series of waves with an average periodicity of 7 min (1). With each wave, translocation toward th...

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Constitutively Active Protein Kinase A Disrupts Motility and Chemotaxis inDictyostelium discoideum

et al. 2003

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“…MLTKs are activated by osmotic shock, and overexpression of MLTK␣, but not MLTK␤, induces the disruption of actin stress fibers and dramatic changes in cell morphology mediated through the p38 MAP kinase pathway (Gotoh et al, 2001). Dictyostelium grows as single-celled amoebae, which, upon starvation, aggregate to form a multicellular organism (Aubry and Firtel, 1999;Chen et al, 1996). Both aggregation and subsequent morphogenesis involve chemotaxis to one or more secreted factors.…”

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DictyosteliumStress-activated Protein Kinase α, a Novel Stress-activated Mitogen-activated Protein Kinase Kinase Kinase-like Kinase, Is Important for the Proper Regulation of the Cytoskeleton

Sun

Firtel

2003

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Mitogen-activated protein kinase cascades regulate various cellular functions, including growth, cell differentiation, development, and stress responses. We have identified a new Dictyostelium kinase (stress-activated protein kinase [SAPK]␣), which is related to members of the mixed lineage kinase class of mitogen-activated protein kinase kinases. SAPK␣ is activated by osmotic stress, heat shock, and detachment from the substratum and by a membrane-permeable cGMP analog, a known regulator of stress responses in Dictyostelium. SAPK␣ is important for cellular resistance to stresses, because SAPK␣ null cells exhibit reduced viability in response to osmotic stress. We found that SAPK␣ mutants affect cellular processes requiring proper regulation of the actin cytoskeleton, including cell motility, morphogenesis, cytokinesis, and cell adhesion. Overexpression of SAPK␣ results in highly elevated basal and chemoattractant-stimulated F-actin levels and strong aggregation and developmental defects, including a failure to polarize and chemotax, and abnormal morphogenesis. These phenotypes require a kinase-active SAPK␣. SAPK␣ null cells exhibit reduced chemoattractant-stimulated F-actin levels, cytokinesis, developmental and adhesion defects, and a motility defect that is less severe than that exhibited by SAPK␣-overexpressing cells. SAPK␣ colocalizes with F-actin in F-actin-enriched structures, including membrane ruffles and pseudopodia during chemotaxis. Although SAPK␣ is required for these F-actin-mediated processes, it is not detectably activated in response to chemoattractant stimulation. INTRODUCTIONThe actin cytoskeleton plays a vital role in numerous cellular processes, such as cell locomotion, phagocytosis, cytokinesis, cell adhesion, cell shape changes, and stress responses. During these processes, the actin cytoskeleton is dynamically changed, a process that involves F-actin polymerization and depolymerization and the reorganization of existing filament networks. Mutations of signaling molecules or structural elements involved in these changes affect cellular processes to various extents.Eukaryotic cells are constantly exposed to stress conditions. To survive, cells adopt various mechanisms to adapt to environmental changes. Mitogen-activated protein kinase (MAPK) pathways regulate cellular responses to external stress in various organisms, including yeast, plants, and mammals (Canman and Kastan, 1996;Jonak et al., 1996;Gustin et al., 1998;Hirt, 2000;Kyriakis and Avruch, 2001;O'Rourke et al., 2002). In Saccharomyces cerevisiae, the wellcharacterized HOG1 MAPK pathway is activated by osmotic stress and leads to gene expression and glycerol production, which is critical for yeast cells to withstand osmotic stress (Gustin et al., 1998;O'Rourke et al., 2002). In mammalian cells, the c-Jun NH 2 -terminal kinase/stress-activated protein kinase (JNK/SAPK1) pathway and the p38/SAPK2 MAP kinase pathway are both activated by diverse stimuli including UV, osmotic, and thermal stresses (Canman and Kastan, 1996;Chang and Kari...

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“…30,31 In particular, the molecular circuit regulating Dictyostelium chemotaxis along cAMP gradients has been modelled as three interconnected modules involving intracellular calcium (Ca 2+ ), inositol 1,4,5-triphosphate (IP 3 ) and the G protein-coupled receptor cAR1, 24,26,[32][33][34][35] as shown in Fig. 1.…”

Section: A New Model For Camp Oscillations In Dictyostelium Exhibits mentioning

confidence: 99%

Computational modelling suggests dynamic interactions between Ca2+, IP3 and G protein-coupled modules are key to robust Dictyostelium aggregation

et al. 2009

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Under conditions of starvation, Dictyostelium cells begin a programme of development during which they aggregate to form a multicellular structure by chemotaxis, guided by propagating waves of cyclic AMP that are relayed robustly from cell to cell. In this paper, we develop and analyse a new model for the intracellular and extracellular cAMP dependent processes that regulate Dictyostelium migration. The model allows, for the first time, a quantitative analysis of the dynamic interactions between calcium, IP 3 and G protein-dependent modules that are shown to be key to the generation of robust cAMP oscillations in Dictyostelium cells. The model provides a mechanistic explanation for the transient increase in cytosolic free Ca 2+ concentration seen in recent experiments with the application of the calmodulin inhibitor calmidazolium (R24571) to Dictyostelium cells, and also allows elucidation of the effects of varying both the conductivity of stretch-activated channels and the concentration of external phosphodiesterase on the oscillatory regime of an individual cell. A rigorous analysis of the robustness of the new model shows that interactions between the different modules significantly reduce the sensitivity of the resulting cAMP oscillations to variations in the kinetics of different Dictyostelium cells, an essential requirement for the generation of the spatially and temporally synchronised chemoattractant cAMP waves that guide Dictyostelium aggregation.

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Integration of Signaling Networks that Regulate Dictyostelium Differentiation

Cited by 151 publications

References 245 publications

Constitutively Active Protein Kinase A Disrupts Motility and Chemotaxis inDictyostelium discoideum

Constitutively Active Protein Kinase A Disrupts Motility and Chemotaxis inDictyostelium discoideum

DictyosteliumStress-activated Protein Kinase α, a Novel Stress-activated Mitogen-activated Protein Kinase Kinase Kinase-like Kinase, Is Important for the Proper Regulation of the Cytoskeleton

Computational modelling suggests dynamic interactions between Ca2+, IP3 and G protein-coupled modules are key to robust Dictyostelium aggregation

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