An intersection of the cAMP/PKA and two-component signal transduction systems in Dictyostelium

Thomason, Peter A.; Traynor, David; Cavet, Guy; Chang, Wen Tsan; Harwood, Adrian J.; Kay, Robert R.

doi:10.1093/emboj/17.10.2838

Cited by 137 publications

(156 citation statements)

References 48 publications

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“…EUKARYOT. 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).…”

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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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“…EUKARYOT. 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).…”

mentioning

confidence: 99%

“…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. As the internal concentration of cAMP increases, so does the activity of PKA.…”

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Constitutively Active Protein Kinase A Disrupts Motility and Chemotaxis inDictyostelium discoideum

et al. 2003

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“…For example, cAMP is a key regulator of Drosophila development by a mechanism in which PKA inhibits the Hedgehog-dependent activation of the Cubitus interruptus transcription factor (22). In Dictyostelium amoebae, extracellular cAMP regulates G-protein-dependent and -independent pathways to control aggregation as well as the activity of GSK-3 and the transcription factors GBF (G-box binding factor) and STAT during multicellular development (23,24).More importantly, cAMP and its effector, PKA, are implicated in a variety of cross-talks between intracellular signaling pathways. It was reported that the exit from mitosis in Xenopus egg extracts required the MPF (maturation-promoting fac-* This work was supported by Korea Research Foundation Grant KRF-2000-015-DS0034.…”

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Cyclic AMP Inhibits Akt Activity by Blocking the Membrane Localization of PDK1

Kim

Jee

Kim

et al. 2001

Journal of Biological Chemistry

172

142

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Akt is a protein serine/threonine kinase that plays an important role in the mitogenic responses of cells to variable stimuli. Akt contains a pleckstrin homology (PH) domain and is activated by phosphorylation at threonine 308 and serine 473. Binding of 3-OH phosphorylated phosphoinositides to the PH domain results in the translocation of Akt to the plasma membrane where it is activated by upstream kinases such as (phosphoinositide-dependent kinase-1 (PDK1). Over-expression of constitutively active forms of Akt promotes cell proliferation and survival, and also stimulates p70 S6 kinase (p70S6K). In many cells, an increase in levels of intracellular cyclic AMP (cAMP) diminishes cell growth and promotes differentiation, and in certain conditions cAMP is even antagonistic to the effect of growth factors. Here, we show that cAMP has inhibitory effects on the phosphatidylinositol 3-kinase/PDK/Akt signaling pathway. cAMP potently inhibits phosphorylation at threonine 308 and serine 473 of Akt, which is required for the protein kinase activities of Akt. cAMP also negatively regulates PDK1 by inhibiting its translocation to the plasma membrane, despite not affecting its protein kinase activities. Furthermore, when we co-expressed myristoylated Akt and PDK1 mutants which constitutively co-localize in the plasma membrane, Akt activity was no longer sensitive to raised intracellular cAMP concentrations. Finally, cAMP was also found to inhibit the lipid kinase activity of PI3K and to decrease the levels of phosphatidylinositol 3,4,5-triphosphate in vivo, which are required for the membrane localization of PDK1. Collectively, these data strongly support the theory that the cAMP-dependent signaling pathway inhibits Akt activity by blocking the coupling between Akt and its upstream regulators, PDK, in the plasma membrane.The phosphatidylinositol 3-kinase (PI3K) 1 -dependent cell signaling pathway has emerged as a key regulatory pathway involved in a number of cellular events (1). Upon activation of growth factor tyrosine kinase receptors, the p85 regulatory subunit of PI3K recruits the p110 catalytic subunit to the plasma membrane (2). The p110 catalytic subunit increases the level of PtdIns-3,4,5-P 3 and phosphatidylinositol 3,4-bisphosphate (PtdIns-3,4-P 2 ), which induce the membrane translocation of PDK1 and Akt (also called PKB or RAC-PK) by binding to the pleckstrin homology domain (3). In the membrane, PDK1 phosphorylates and activates Akt in a PtdIns-3,4,5-P 3 -or PtdIns-3,4-P 2 -dependent manner (4, 5). By a mechanism that involves phospholipase C (6), activated Akt is released from the membrane and phosphorylates various targets.This complex and unique signaling pathway has been implicated in a variety of cellular events such as cell proliferation and survival (1, 7). Previously, it has been shown that various survival factors, such as nerve growth factor, require the activation of PI3K to prevent various cell types from undergoing apoptosis (8, 9). The mechanism by which the PI3K pathway protects cells from programm...

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“…Algumas das proteínas quinases já identificadas como a PKA, as MAP quinases e a GskA mencionadas acima foram diretamente implicadas no controle do crescimento e/ou desenvolvimento (Nuckolls et al, 1996;Loomis et al, 1997;Singleton et al, 1998;Thomason et al, 1998;Widmann et al, 1999). Ao menos oito tirosinas quinases e três tirosinas fosfatases já foram identificadas, sendo que as primeiras são distintas das tirosina quinases de mamíferos (Tan & Spudich, 1990;Howard et al, 1992;Ramalingam et al, 1993;Howard et al, 1994;Adler et al, 1996;Gamper et al, 1996;Kim et al, 1999).…”

Section: Fosforilação Reversível De Proteínas Em Dictyostelium Discoiunclassified

Caracterização molecular da proteína DdI-2 e mapeamento de seus domínios de interação com a proteína fosfatase do tipo-1 de Dictyostelium discoideum

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An intersection of the cAMP/PKA and two-component signal transduction systems in Dictyostelium

Cited by 137 publications

References 48 publications

Constitutively Active Protein Kinase A Disrupts Motility and Chemotaxis inDictyostelium discoideum

Constitutively Active Protein Kinase A Disrupts Motility and Chemotaxis inDictyostelium discoideum

Cyclic AMP Inhibits Akt Activity by Blocking the Membrane Localization of PDK1

Caracterização molecular da proteína DdI-2 e mapeamento de seus domínios de interação com a proteína fosfatase do tipo-1 de Dictyostelium discoideum

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