Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An early decision that a newly formed aggregate of Dictyostelium cells must make is whether to form a migrating slug or to proceed through culmination, the process of forming the mature fruiting body. The choice between these alternative morphological pathways is influenced by external and internal cues. dhkC was identified as a potential hybrid sensor kinase possessing domains homologous to the histidine kinase and receiver motifs of two-component signaling systems. Null strains of dhkC show a rapidly developing phenotype for aggregation through finger formation, and culmination commences immediately thereafter and proceeds at a normal rate to generate typical fruiting bodies. Ammonia, an endogenous regulator of the slug versus culmination choice, results in a prolonged slug stage for wild-type strains while the dhkC- strain bypasses the slug stage in the presence or absence of ammonia. Conversely, expression in wild-type cells of a modified DHKC protein composed of only the histidine kinase domain results in normal timing through early aggregation, but subsequent development is significantly delayed. The resulting fingers, once formed, readily convert to slugs that do not undergo culmination but instead migrate until their energy sources are depleted. The slugger phenotype is dependent on the presence of a functional response regulator REGA, and it is rescued by exogenously supplied cAMP. Together, the results indicate that DHKC contributes to the integration of environmental and cellular signals so that the appropriate choice is made between slug formation and culmination. We suggest that DHKC may function as a sensor for ammonia, and that it is the initial component of a phosphorelay signaling system that may modulate the activity of cAMP-dependent protein kinase to either inhibit or promote culmination. Additionally, dhkC- spores were found to be defective in germination, indicating a role for the DHKC signaling pathway in activating spore germination.
 ...
PMID:The histidine kinase dhkC regulates the choice between migrating slugs and terminal differentiation in Dictyostelium discoideum. 980 85

Receptor-mediated activation of adenylyl cyclase (ACA) in Dictyostelium requires CRAC protein. Upon translocation to the membrane, this pleckstrin homology (PH) domain protein stimulates ACA and thereby mediates developmental aggregation. CRAC may also have roles later in development since CRAC-null cells can respond to chemotactic signals and participate in developmental aggregation when admixed with wild-type cells, but they do not complete development within such chimeras. To test whether the role of CRAC in postaggregative development is related to the activation of ACA, chemotactic aggregation was bypassed in CRAC-null cells by activating the cAMP-dependent protein kinase (PKA). While such strains formed mounds, they did not complete fruiting body morphogenesis or form spores. Expression of CRAC in the prespore cells of these strains rescued sporulation and fruiting body formation. This later function of CRAC does not appear to require its PH domain since the C-terminal portion of the protein (CRAC-DeltaPH) can substitute for full-length CRAC in promoting spore cell formation and morphogenesis. No detectable ACA activation was observed in any of the CRAC-null strains rescued by PKA activation and expression of CRAC-DeltaPH. Finally, we found that the development of CRAC-null ACA-null double mutants could be rescued by the activation of PKA together with the expression of CRAC-DeltaPH. Thus, there appears to be a required function for CRAC in postaggregative development that is independent of its previously described function in the ACA activation pathway.
 ...
PMID:Multiple developmental roles for CRAC, a cytosolic regulator of adenylyl cyclase. 1007 37

During the last stage of Dictyostelium development a motile, cylindrical slug transforms into an immotile, stalked fruiting body and the constituent cells change from amoebae to either refractile spores or vacuolated stalk cells. Analysis of this process using genetics and simple culture techniques is becoming a powerful way of investigating a number of conserved signal transduction processes. A common pathway activating cAMP-dependent protein kinase (PKA) triggers the maturation of spore cells and those stalk cells forming the stalk. It uses a eukaryotic version of the 'bacterial' two-component phospho-relay system to control cAMP breakdown. A second pathway, inhibiting the GSK3 protein kinase, might control the maturation of a distinct set of stalk cells at the base of the fruiting body.
 ...
PMID:Taking the plunge. Terminal differentiation in Dictyostelium. 1008 28

The avian retroviral v-myb gene and its cellular homologues throughout the animal and plant kingdoms contain a conserved DNA binding domain. We have isolated an insertional mutant of Dictyostelium unable to switch from slug migration to fruiting body formation i.e. unable to culminate. The gene that is disrupted, mybC, codes for a protein with a myb-like domain that is recognized by an antibody against the v-myb repeat domain. During development of myb+ cells, mybC is expressed only in prestalk cells. When developed together with wild-type cells mybC- cells are able to form both spores and stalk cells very efficiently. Their developmental defect is also bypassed by overexpressing cAMP-dependent protein kinase. However even when their defect is bypassed, mybC null slugs and culminates produce little if any of the intercellular signalling peptides SDF-1 and SDF-2 that are believed to be released by prestalk cells at culmination. We propose that the mybC gene product is required for an intercellular signaling process controlling maturation of stalk cells and spores and that SDF-1 and/or SDF-2 may be implicated in this process.
 ...
PMID:A myb-related protein required for culmination in Dictyostelium. 1033 90

When nutrients are depleted, Dictyostelium cells undergo cell cycle arrest and initiate a developmental program that ensures survival. The YakA protein kinase governs this transition by regulating the cell cycle, repressing growth-phase genes and inducing developmental genes. YakA mutants have a shortened cell cycle and do not initiate development. A suppressor of yakA that reverses most of the developmental defects of yakA- cells, but none of their growth defects was identified. The inactivated gene, pufA, encodes a member of the Puf protein family of translational regulators. Upon starvation, pufA- cells develop precociously and overexpress developmentally important proteins, including the catalytic subunit of cAMP-dependent protein kinase, PKA-C. Gel mobility-shift assays using a 200-base segment of PKA-C's mRNA as a probe reveals a complex with wild-type cell extracts, but not with pufA- cell extracts, suggesting the presence of a potential PufA recognition element in the PKA-C mRNA. PKA-C protein levels are low at the times of development when this complex is detectable, whereas when the complex is undetectable PKA-C levels are high. There is also an inverse relationship between PufA and PKA-C protein levels at all times of development in every mutant tested. Furthermore, expression of the putative PufA recognition elements in wild-type cells causes precocious aggregation and PKA-C overexpression, phenocopying a pufA mutation. Finally, YakA function is required for the decline of PufA protein and mRNA levels in the first 4 hours of development. We propose that PufA is a translational regulator that directly controls PKA-C synthesis and that YakA regulates the initiation of development by inhibiting the expression of PufA. Our work also suggests that Puf protein translational regulation evolved prior to the radiation of metazoan species.
 ...
PMID:Starvation promotes Dictyostelium development by relieving PufA inhibition of PKA translation through the YakA kinase pathway. 1037 15

Activation of cAMP-dependent protein kinase (PKA) triggers terminal differentiation in Dictyostelium, without an obvious requirement for the G-protein-coupled adenylyl cyclase, ACA, or the osmosensory adenylyl cyclase, ACG. A third adenylyl cyclase, ACB, was recently detected in rapidly developing mutants. The specific characteristics of ACA, ACG, and ACB were used to determine their respective activities during development of wild-type cells. ACA was highly active during aggregation, with negligible activity in the slug stage. ACG activity was not present at significant levels until mature spores had formed. ACB activity increased strongly after slugs had formed with optimal activity at early fruiting body formation. The same high activity was observed in slugs of ACG null mutants and ACA null mutants that overexpress PKA (acaA/PKA), indicating that it was not due to either ACA or ACG. The detection of high adenylyl cyclase activity in acaA/PKA null mutants contradicts earlier conclusions (B. Wang and A. Kuspa, Science 277, 251-254, 1997) that these mutants can develop into fruiting bodies in the complete absence of cAMP. In contrast to slugs of null mutants for the intracellular cAMP-phosphodiesterase REGA, where both intact cells and lysates show ACB activity, wild-type slugs only show activity in lysates. This indicates that cAMP accumulation by ACB in living cells is controlled by REGA. Both REGA inhibition and PKA overexpression cause precocious terminal differentiation. The developmental regulation of ACB and its relationship to REGA suggest that ACB activates PKA and induces terminal differentiation.
 ...
PMID:Fingerprinting of adenylyl cyclase activities during Dictyostelium development indicates a dominant role for adenylyl cyclase B in terminal differentiation. 1041 94

In Dictyostelium amoebae, cell-type differentiation, spatial patterning, and morphogenesis are controlled by a combination of cell-autonomous mechanisms and intercellular signaling. A chemotactic aggregation of approximately 10(5) cells leads to the formation of a multicellular organism. Cell-type differentiation and cell sorting result in a small number of defined cell types organized along an anteroposterior axis. Finally, a mature fruiting body is created by the terminal differentiation of stalk and spore cells. Analysis of the regulatory program demonstrates a role for several molecules, including GSK-3, signal transducers and activators of transcription (STAT) factors, and cAMP-dependent protein kinase (PKA), that control spatial patterning in metazoans. Unexpectedly, two component systems containing histidine kinases and response regulators also play essential roles in controlling Dictyostelium development. This review focuses on the role of cAMP, which functions intracellularly to mediate the activity of PKA, an essential component in aggregation, cell-type specification, and terminal differentiation. Cytoplasmic cAMP levels are controlled through both the regulated activation of adenylyl cyclases and the degradation by a phosphodiesterase containing a two-component system response regulator. 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 and STATa during multicellular development. The integration of these pathways with others regulated by the morphogen DIF-1 to control cell fate decisions are discussed.
 ...
PMID:Integration of signaling networks that regulate Dictyostelium differentiation. 1061 70

cAMP-dependent protein kinase (PKA) is an essential regulator of gene expression and cell differentiation during multicellular development of Dictyostelium discoideum. Here we show that PKA activity also regulates gene expression during the growth phase and at the transition from growth to development. Overexpression of PKA leads to overexpression of the discoidinIgamma promoter, while expression of the discoidinIgamma promoter is reduced when PKA activity is reduced, either by expression of a dominant negative mutant of the regulatory subunit or by disruption of the gene for the catalytic subunit (PKA-C). The discoidin phenotype of PKA-C null cells is cell autonomous. In particular, normal secretion of discoidin-inducing factors was demonstrated. In addition, PKA-C null cells are able to respond to media conditioned by PSF and CMF. We conclude that PKA is a major activator of discoidin expression. However, it is not required for production or transduction of the inducing extracellular signals. Therefore, PKA-dependent and PKA-independent pathways regulate the expression of the discoidin genes.
 ...
PMID:Role of cAMP-dependent protein kinase during growth and early development of Dictyostelium discoideum. 1077 94

Mitogen-activated protein (MAP)-kinase extracellular signal regulated kinase (ERK2) is essential for regulation of the intracellular cyclic adenosine monophosphate (cAMP) level in Dictyostelium. The mutant lacking ERK2, erk2-null, is arrested at the pre-aggregation stage, but develops into a fruiting body in a mixed population of wild-type and mutant cells. This fact implies that wild-type cells provide a certain factor that is missing in erk2-null. It was clarified that both wild-type strains KAx3 and Ax2 secreted a diffusible factor that enables erk2-null to develop. The fruiting body formed from erk2-null cells was smaller than that formed by the wild-type cells and consisted of a small sorus supported by a slender stalk with a single row of vacuolated stalk cells. The resulting spores were able to germinate and multiply on a bacterial lawn, but they were unable to develop unless the factor was provided. After 8 h of starvation, wild-type cells started to secrete the factor, which had a molecular mass of less than 3 kDa and was heat stable. The effect of this factor could not be mimicked by either cAMP or folate. Adenylyl cyclase A and cell surface cAMP receptors cAR1 and cAR3 were all indispensable components for the factor to function. Considering the molecular mass and the mode of action, this factor could be a novel one. Possible targets of this factor are discussed in terms of cAMP-dependent protein kinase activation.
 ...
PMID:A diffusible factor involved in MAP-kinase ERK2-regulated development of Dictyostelium. 1091 Jan 34

It has been previously reported that the differentiating wild-type cells of Dictyostelium discoideum secrete a diffusible factor or factors that are able to rescue the developmental defect in the mutant lacking extracellular signal-regulated kinase 2 (ERK2), encoded by the gene erkB. In the present study, it is demonstrated that differentiation-inducing factor-1 (DIF-1) for stalk cells can mimic the role of the factor(s) and the mechanism of the action of DIF-1 in the erkB null mutant is also discussed. The mutant usually never forms multicellular aggregates, because of its defect in cyclic adenosine monophosphate (cAMP) signaling. In the presence of 100 nM DIF-1, however, the mutant cells formed tiny slugs, which eventually developed into small fruiting bodies. In contrast, DIF-1 never rescued the developmental arrest of other Dictyostelium mutants lacking adenylyl cyclase A (ACA), cAMP receptors cAR1 and cAR3, heterotrimeric G-protein, the cytosolic regulator of ACA, or the catalytic subunit of cAMP-dependent protein kinase (PKA-C). Most importantly, it was found that DIF-1 did not affect the cellular cAMP level, but rather elevated the transcriptional level of pka during the development of erkB null cells. These results suggest that DIF-1 may rescue the developmental defect in erkB null cells via the increase in PKA activity, thus giving the first conclusive evidence that DIF-1 plays a crucial role in the early events of Dictyostelium development as well as in prestalk and stalk cell induction.
 ...
PMID:A novel role of differentiation-inducing factor-1 in Dictyostelium development, assessed by the restoration of a developmental defect in a mutant lacking mitogen-activated protein kinase ERK2. 1104 94


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>