AMP-activated Protein Kinase Phosphorylates and Desensitizes Smooth Muscle Myosin Light Chain Kinase

Horman, Sandrine; Morel, Nicole; Vertommen, Didier; Hussain, Nusrat; Neumann, Dietbert; Beauloye, Christophe; Najjar, Nicole El; Forcet, Christelle; Viollet, Benoı̂t; Walsh, Michael P.; Hue, Louis; Rider, Mark H.

doi:10.1074/jbc.m802053200

Cited by 108 publications

(139 citation statements)

References 41 publications

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“…STO-609, an inhibitor of CaMKK␤, has been used to demonstrate the role of CaMKK␤ in AMPK activation (40,55,56). Here, we found that STO-609 had no effect on the increase in O-GlcNAc, even at concentrations as high as 80 M, suggesting that CaMKK␤-mediated AMPK activation was not a contributing factor in the response to glucose deprivation.…”

Section: Discussionmentioning

confidence: 55%

Glucose Deprivation-induced Increase in Protein O-GlcNAcylation in Cardiomyocytes Is Calcium-dependent

Zou

Zhu-Mauldin

Marchase

et al. 2012

Journal of Biological Chemistry

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Background: Levels of cellular protein O-GlcNAc modification increase in response to stress, but mechanism not understood. Results: Glucose deprivation and heat shock-induced increase in O-GlcNAcylation are attenuated by CaMKII inhibition. Conclusion: CaMKII activation plays a key role in regulating the stress-induced increase in O-GlcNAc. Significance: Understanding the regulation of O-GlcNAcylation is critical in determining its role in cellular stress responses.

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Section: Discussionmentioning

confidence: 55%

Glucose Deprivation-induced Increase in Protein O-GlcNAcylation in Cardiomyocytes Is Calcium-dependent

Zou

Zhu-Mauldin

Marchase

et al. 2012

Journal of Biological Chemistry

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“…In contrast to this observed AMPK-MRLC pathway, deletion of Lkb1 in the pancreatic epithelium does not lead to a decrease in p-MRLC (Ser19) . Moreover, the MRLC pathway is inhibited rather than activated by AMPK in vascular smooth muscle cells (Horman et al, 2008).…”

Section: Mechanisms Of Polarity Controlmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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“…The AMPK-null mutation in Drosophila is lethal, producing severe defects in cell polarity and mitosis; it was shown that nonmuscle myosin regulatory light chain was phosphorylated directly by AMPK, and the expression of a phosphomimetic light chain was found to rescue the cell polarity and mitosis phenotype. 49 AMPK phoshorylates and desensitizes smooth muscle myosin light chain kinase 50 and has been shown to be involved in the regulation of Drosophila visceral smooth muscle via myosin light chain phosphorylation. 51 In mammalian cells, both the activated ␣ subunit and the ␥2 subunit have been localized to distinct position in the cytokinetic apparatus, 52,53 and in epithelial cells the kinase has also been shown to mediate reorganization of the actin cytoskeleton.…”

Section: Discussionmentioning

confidence: 99%

“…All data acquisition and analysis were performed in a blinded fashion. pCa 50 in the recording chamber. LV myocyte length was measured by using a video-edge detection system (IonOptix Corp, field stimulation at 3Hz).…”

Section: Force Measurements In Skinned Preparationsmentioning

confidence: 99%

AMP-Activated Protein Kinase Phosphorylates Cardiac Troponin I and Alters Contractility of Murine Ventricular Myocytes

Oliveira

Zhang²,

Solis

et al. 2012

Circulation Research

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Rationale: AMP-activated protein kinase (AMPK) is an important regulator of energy balance and signaling in the heart. Mutations affecting the regulatory ␥2 subunit have been shown to cause an essentially cardiacrestricted phenotype of hypertrophy and conduction disease, suggesting a specific role for this subunit in the heart.Objective: The ␥ isoforms are highly conserved at their C-termini but have unique N-terminal sequences, and we hypothesized that the N-terminus of ␥2 may be involved in conferring substrate specificity or in determining intracellular localization. Methods and Results:A yeast 2-hybrid screen of a human heart cDNA library using the N-terminal 273 residues of ␥2 as bait identified cardiac troponin I (cTnI) as a putative interactor. In vitro studies showed that cTnI is a good AMPK substrate and that Ser150 is the principal residue phosphorylated. Furthermore, on AMPK activation during ischemia, Ser150 is phosphorylated in whole hearts. Using phosphomimics, measurements of actomyosin ATPase in vitro and force generation in demembraneated trabeculae showed that modification at Ser150 resulted in increased Ca 2؉ Key Words: familial hypertrophic cardiomyopathy Ⅲ myocardial contractility Ⅲ phosphorylation A MP-activated protein kinase (AMPK) is a crucial component of a highly conserved serine/threonine protein kinase cascade central to the control of energy balance at the cellular and whole-body levels. 1,2 AMPK exists as a ␣␤␥ heterotrimer, with ␣ being the catalytic subunit, and the ␤ and ␥ subunits performing structural and regulatory functions. Isoforms of all subunits have been identified (␣1, ␣2, ␤1, ␤2, ␥1, ␥2, and ␥3), each being encoded by a different gene (PRKAA1, PRKAA2, PRKAB1, PRKAB2, PRKAG1, PRKAG2, and PRKAG3, respectively). The ␣ subunits consist of a typical serine/threonine protein kinase domain at the N-terminus (which also contains the critical phosphorylation site for AMPK activation, Thr172 3 ) and a C-terminal domain involved in the binding of the ␤ and ␥ subunits. 1,2 The ␤ subunits are myristoylated at their N-terminus, contain a conserved C-terminal domain that is involved in binding of the ␣ and ␥ subunits, and a carbohydrate binding domain. The carbohydrate binding domain may allow AMPK to sense the status of cellular energy reserves in the form of glycogen in addition to responding to AMP/ATP levels. 4 The ␥ subunits have a high degree of homology in their C-terminal Original received October 31, 2011; revision received March 14, 2012; accepted March 19, 2012. In February 2012 sequences, all containing 2 pairs of highly conserved cystathionine ␤-synthase domains, which have been shown to be directly involved in the binding of adenine nucleotides. [5][6][7] In contrast, their N-terminal regions are highly variable, with ␥2 and ␥3 possessing different long N-terminal extensions compared with the shorter ␥1 isoform (Figure 1). The ␥2 and ␥3 N-terminal sequences appear to be unique in that they do not share sequence identity with each other nor with any known protein. ...

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AMP-activated Protein Kinase Phosphorylates and Desensitizes Smooth Muscle Myosin Light Chain Kinase

Cited by 108 publications

References 41 publications

Glucose Deprivation-induced Increase in Protein O-GlcNAcylation in Cardiomyocytes Is Calcium-dependent

Glucose Deprivation-induced Increase in Protein O-GlcNAcylation in Cardiomyocytes Is Calcium-dependent

LKB1; linking cell structure and tumor suppression

AMP-Activated Protein Kinase Phosphorylates Cardiac Troponin I and Alters Contractility of Murine Ventricular Myocytes

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