Components of a Calmodulin-dependent Protein Kinase Cascade

Anderson, Kristin A.; Means, Raylene L.; Huang, Qi-Hui; Kemp, Bruce E.; Goldstein, Elaine G.; Selbert, Michele A.; Edelman, Arthur M.; Fremeau, Robert T.; Means, Anthony R.

doi:10.1074/jbc.273.48.31880

Cited by 237 publications

(122 citation statements)

References 52 publications

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“…Biochemical data demonstrate that CaMKIV is a substrate for CaMKK␤ in vitro and that CaMKK␤ enhances the ability of CaMKIV to drive CREBmediated transcription in vivo (9). Taken together, these results present a conundrum because the activating kinase seems to be spatially separated from its substrate by the nuclear membrane.…”

Section: Discussionsupporting

confidence: 51%

“…Because the catalytically inactive CaMKIV and the CaMKK colocalize in the cytoplasm, we speculate that catalytically inactive mutants inhibit wild-type CaMKIV by sequestering CaMKK in the cytoplasm. This would reduce the ability of CaMKK to bind to and activate wild-type CaMKIV, events that are required for CaMKIV to drive CREB-mediated transcription (9). Second, we find that catalytically inactive forms of either AMPK or AKT (10), two other kinases activated by CaMKK, do not inhibit the ability of wild-type CaMKIV to drive CREB-mediated transcription (Fig.…”

mentioning

confidence: 69%

“…This enzyme exhibits low protein kinase activity in vitro (4,7). An activating protein kinase, calcium/calmodulin-dependent protein kinase kinase (CaMKK), binds to the Ca 2ϩ / CaM⅐CaMKIV complex and phosphorylates CaMKIV on Thr 196 in the activation loop (8)(9)(10). Activation loop phosphorylation is required to activate CaMKIV fully and render the enzyme capable of phosphorylating nuclear proteins involved in transcription such as the cAMP response element-binding protein (CREB) and the CREB-binding protein (2,11,12).…”

mentioning

confidence: 99%

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Catalytic Activity Is Required for Calcium/Calmodulin-dependent Protein Kinase IV to Enter the Nucleus

Lemrow

Anderson

Joseph

et al. 2004

Journal of Biological Chemistry

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Calcium/calmodulin-dependent protein kinase IV (CaMKIV) is a nuclear protein kinase that responds to acute rises in intracellular calcium by phosphorylating and activating proteins involved in transcription. Consistent with these roles, CaMKIV is found predominantly in the nucleus of cells in which it is expressed. Here we evaluate nuclear entry of CaMKIV and demonstrate that the protein kinase homology domain is both necessary and sufficient for nuclear localization. Unexpectedly, although catalytic activity is required for nuclear translocation, it is not required for CaMKIV to interact with the nuclear adaptor protein, importin-␣. Because the catalytically inactive molecules remain in the cytoplasm, these data suggest that this interaction is not sufficient for nuclear entry. We evaluated a role for other proteins known to interact with CaMKIV in regulation of its nuclear entry. Although our data do not support a role for calmodulin or protein phosphatase 2A, the catalytically inactive CaMKIV proteins interact more avidly with CaM-dependent protein kinase kinase (CaMKK), which is restricted to the cytoplasm. We find that the catalytically inactive proteins do not inhibit nuclear entry of wild-type CaMKIV but do inhibit the ability of the wild-type protein kinase to stimulate cyclic AMP response element-binding protein-mediated tran-

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Section: Discussionsupporting

confidence: 51%

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confidence: 69%

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confidence: 99%

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Catalytic Activity Is Required for Calcium/Calmodulin-dependent Protein Kinase IV to Enter the Nucleus

Lemrow

Anderson

Joseph

et al. 2004

Journal of Biological Chemistry

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“…Therefore, we chose the CaMKIV Subst 318 -329 mutant to test the role of the CaMKIV/PP2A interaction by comparing it with WT kinase in a cell-based assay. The cell based assay used was the CREB transcription assay in which cells are cotransfected with GAL4-CREB, a GAL4-luciferase reporter, and CaMKIV (35). After stimulation of the cells with ionomycin to increase the intracellular Ca 2ϩ concentration, cell extracts were made, from which luciferase activity was measured.…”

Section: Resultsmentioning

confidence: 99%

“…The cells were stimulated with 2 M ionomycin (calcium salt from Calbiochem, 407952) the following evening for ϳ16 h and then lysed. Luciferase and ␤-galactosidase activities in cell extracts were determined within 1-2 h as previously described (35). Transfection efficiency was normalized by ␤-galactosidase activity, and the control transfection was empty pSG5 vector (Stratagene).…”

Section: Cells and Cellmentioning

confidence: 99%

Regulation and Function of the Calcium/Calmodulin-dependent Protein Kinase IV/Protein Serine/Threonine Phosphatase 2A Signaling Complex

Anderson

Noeldner

Reece

et al. 2004

Journal of Biological Chemistry

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Sending signals from the synapse to the nucleus: Possible roles for CaMK, Ras/ERK, and SAPK pathways in the regulation of synaptic plasticity and neuronal growth

1999

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The ability to learn and form memories depends on specific patterns of synaptic activity and is in part transcription dependent. However, the signal transduction pathways that connect signals generated at synapses with transcriptional responses in the nucleus are not well understood. In the present report, we discuss three signal transduction pathways: the Ca(2+)/calmodulin-dependent kinase (CaMK) pathway, the Ras/ERK pathway, and the SAPK pathways that might function to couple synaptic activity to long-term adaptive responses, in part through the regulation of new gene expression. Evidence suggests that these pathways become activated in response to stimuli that regulate synaptic function such as the influx of extracellular Ca(2+) and certain neurotrophin growth factors such as brain-derived neurotrophic factor. Once activated, the CaMK, Ras/ERK, and SAPK pathways lead to the phosphorylation and activation of transcription factors in the nucleus such as the cyclic AMP response element binding protein (CREB). Genes regulated by CREB or other transcription factor targets of the CaMK, Ras/ERK, and SAPK pathways could mediate important adaptive responses to changes in synaptic activity such as changes in synaptic strength and the regulation of neuronal survival and death.

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Components of a Calmodulin-dependent Protein Kinase Cascade

Cited by 237 publications

References 52 publications

Catalytic Activity Is Required for Calcium/Calmodulin-dependent Protein Kinase IV to Enter the Nucleus

Catalytic Activity Is Required for Calcium/Calmodulin-dependent Protein Kinase IV to Enter the Nucleus

Regulation and Function of the Calcium/Calmodulin-dependent Protein Kinase IV/Protein Serine/Threonine Phosphatase 2A Signaling Complex

Sending signals from the synapse to the nucleus: Possible roles for CaMK, Ras/ERK, and SAPK pathways in the regulation of synaptic plasticity and neuronal growth

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