The Ca2+/Calmodulin-dependent Protein Kinase Kinases Are AMP-activated Protein Kinase Kinases

Hurley, Rebecca L.; Anderson, Kristin A.; Franzone, Jeanne M.; Kemp, Bruce E.; Means, Anthony R.; Witters, Lee A.

doi:10.1074/jbc.m503824200

Cited by 920 publications

(765 citation statements)

References 31 publications

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“…AMPK activation was originally proposed to be dependent on Thr172 phosphorylation via action of upstream kinases including LKB1, 43,44 calmodulin-dependent protein kinase kinase II␤, 45 and Tak1. 46 However, Xie et al 47 suggested that LKB1 actually acts downstream of Tak1 in mouse fibroblasts.…”

Section: Rescue Of Defective Function Requires Ampk Activationmentioning

confidence: 99%

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Cieslik

Trial

Entman

2011

The American Journal of Pathology

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Cardiac fibroblasts are the most prevalent cell type in the heart. These cells exert a critical role in regulating normal myocardial function and in the adverse myocardial remodeling that occurs after myocardial infarction (MI). 1 Irreversible cardiomyocyte damage owing to cessation of oxygen supply during MI leads to necrosis, which stimulates inflammatory reactions that trigger reparative pathways and activate cells to form a scar. Cytokines released by inflammatory infiltrating leukocytes promote endogenous mesenchymal stem cell (MSC) proliferation and migration toward the infarct site, followed by differentiation into fibroblasts that deposit scar-forming collagen. The fibroblasts mature into myofibroblasts, expressing scar-contracting ␣-smooth muscle actin (␣-SMA). 2 Resident fibroblasts also become activated and participate in this process. After several weeks, a mature scar is formed, and most of the myofibroblasts undergo apoptosis. [3][4][5] We have previously established in a model of mouse MI that, compared with young animals, aged mice demonstrate greater infarct expansion and less effective myocardial repair. 6 Defective scar formation arises from a decreased number of myofibroblasts and diminished collagen deposition in the infarct, which results in a structurally unstable scar formed by loose connective tissue. 7 Evidence indicates that multipotent cells can be generated in vitro from several adult organs including the heart. 8 Tissue-resident progenitor cells of mesenchymal origin can differentiate into myogenic, adipocytic, chondrocytic, osteoblastic, and fibroblastic lineages. 9 -11 The potential of those stem cells to differentiate decreases

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Section: Rescue Of Defective Function Requires Ampk Activationmentioning

confidence: 99%

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Cieslik

Trial

Entman

2011

The American Journal of Pathology

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“…Surprisingly, the AMPKa-mediated repression of p73a activity was independent of its kinase activity as shown using AICAR, a known agonist of AMPK, and various AMPKa2 mutants (D157A and K45R, dominant negatives; T172A, inactive; and T174D, constitutively active). It was recently suggested that AMPK can be activated by Ca 2 þ /CaM-dependent protein kinase kinase independently of AMP (Hawley et al, 2005;Hurley et al, 2005;Woods et al, 2005). Similar to AICAR, STO-609, a selective inhibitor of Ca 2 þ /CaMdependent protein kinase kinase, was not effective in the repression of p73a by AMPKa (data not shown).…”

Section: Discussionmentioning

confidence: 87%

“…AMPK has been primarily described as a metabolic sensor that responds to intracellular ATP depletion induced by various metabolic stresses, and it is directly activated by increases in the AMP:ATP ratio (Hardie et al, 1998(Hardie et al, , 1999Kemp et al, 1999). Recent studies suggest that it can also be activated by upstream AMPK kinases such as the serine/threonine kinase LKB1, which phosphorylates the a subunit of AMPK at Thr 174 (at Thr 172 for a2) (Woods et al, 2003;Lizcano et al, 2004;Shaw et al, 2004), and possibly by Ca 2 þ /CaMdependent protein kinase kinase, which functions independently of AMP but phosphorylates the same residue in AMPK (Hawley et al, 2005;Hurley et al, 2005;Woods et al, 2005). Once activated, AMPK phosphorylates several target proteins, which are mostly cytoplasmic enzymes involved in glucose and lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Kinase activity-independent suppression of p73α by AMP-activated kinase α (AMPKα)

et al. 2008

Oncogene

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Although p73a induces many of the same cellular events as p53, it is structurally distinct from p53 in that it possesses a unique COOH-terminal domain. To dissect the function of this domain, we performed yeast twohybrid screening of a HeLa cDNA library using residues 552-636 of p73a as bait. Among the clones that showed a specific interaction with p73a was AMP-activated protein kinase a (AMPKa). Additional yeast two-hybrid assays indicated that the bc-binding domain of AMPKa is critical for the interaction with p73a. The interaction was further confirmed in vitro by glutathione S-transferase pull-down, and in vivo by immunoprecipitation and immunofluorescence microscopy. Transient coexpression of AMPKa resulted in downregulation of the effect of p73a, but not of p53, on various p53-responsive promoters. Chromatin immunoprecipitation indicated p73a-dependent recruitment of AMPKa to the p21WAF1 promoter. Treatment with 5-aminoimidazole-4-carboxamide ribonucleotide, an agonist of AMPKa, and expression of dominant-negative versions of AMPKa revealed that the repression of p73a was independent of AMPKa kinase activity. In addition, cisplatin-induced growth repression was impaired when AMPKa was overexpressed. Upon the knock down of AMPKa by siRNA, the induction of p21WAF1 by p73a was significantly increased. Taken together, these data indicate that AMPKa specifically regulates p73a by a direct interaction without affecting its phosphorylation status. From these data, we speculate that AMPKa may provide a molecular clue to understand the repressive role of the C-terminus of p73a in transcription and DNA damage response.

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“…Similar to LKB1, CaMKKh could also directly activate AMPK by phosphorylation of T172 (27)(28)(29). To determine if CaMKKh contributed to PIA-induced AMPK phosphorylation at this residue, we pretreated LKB1-wt (H1155) and LKB1-mutant (H157 and A549) NSCLC cells with an inhibitor of CAMKK, STO-609 (30).…”

Section: Resultsmentioning

confidence: 99%

“…For example, activators of AMPK such as AICAR and metformin activate AMPK by an LKB1-dependent mechanism (7,8). Although 2-deoxyglucose can activate AMPK in the absence of LKB1 (28), this compound significantly alters the intracellular AMP/ATP ratio, and the level of AMPK activation induced by 2-deoxyglucose is directly related to the presence of LKB1 (22,31). Moreover, 2-deoxyglucose is unlikely to activate AMPK in vivo because millimolar concentrations of 2-deoxyglucose are required to activate AMPK in cultured cells, which is not likely to be achievable in vivo.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol Ether Lipid Analogues Induce AMP-Activated Protein Kinase–Dependent Death in LKB1-Mutant Non–Small Cell Lung Cancer Cells

et al. 2008

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Loss of function of the tumor suppressor LKB1 occurs in 30% to 50% of lung adenocarcinomas. Because LKB1 activates AMP-activated protein kinase (AMPK), which can negatively regulate mTOR, AMPK activation might be desirable for cancer therapy. However, no known compounds activate AMPK independently of LKB1 in vivo, and the usefulness of activating AMPK in LKB1-mutant cancers is unknown. Here, we show that lipid-based Akt inhibitors, phosphatidylinositol ether lipid analogues (PIA), activate AMPK independently of LKB1. PIAs activated AMPK in LKB1-mutant non-small cell lung cancer (NSCLC) cell lines with similar concentration dependence as that required to inhibit Akt. However, AMPK activation was independent of Akt inhibition. AMPK activation was a major mechanism of mTOR inhibition. To assess whether another kinase capable of activating AMPK, CaMKKB, contributed to PIA-induced AMPK activation, we used an inhibitor of CaMKK, STO-609. STO-609 inhibited PIA-induced AMPK activation in LKB1-mutant NSCLC cells, and delayed AMPK activation in wild-type LKB1 NSCLC cells. In addition, AMPK activation was not observed in NSCLC cells with mutant CaMKKB, suggesting that CaMKKB contributes to PIA-induced AMPK activation in cells. AMPK activation promoted PIA-induced cytotoxicity because PIAs were less cytotoxic in AMPKAÀ/À murine embryonic fibroblasts or LKB1-mutant NSCLC cells transfected with mutant AMPK. This mechanism was also relevant in vivo. Treatment of LKB1-mutant NSCLC xenografts with PIA decreased tumor volume by f50% and activated AMPK. These studies show that PIAs recapitulate the activity of two tumor suppressors (PTEN and LKB1) that converge on mTOR. Moreover, they suggest that PIAs might have utility in the treatment of LKB1-mutant lung adenocarcinomas.

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The Ca2+/Calmodulin-dependent Protein Kinase Kinases Are AMP-activated Protein Kinase Kinases

Abstract: ؊/؊ murine embryo fibroblasts. These data indicate that the CaMKKs function in intact cells as AMPKKs, predicting wider roles for these kinases in regulating AMPK activity in vivo.

Cited by 920 publications

References 31 publications

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Kinase activity-independent suppression of p73α by AMP-activated kinase α (AMPKα)

Phosphatidylinositol Ether Lipid Analogues Induce AMP-Activated Protein Kinase–Dependent Death in LKB1-Mutant Non–Small Cell Lung Cancer Cells

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