Mimicking Phosphorylation of αB-Crystallin on Serine-59 Is Necessary and Sufficient to Provide Maximal Protection of Cardiac Myocytes From Apoptosis

Morrison, Lisa E.; Hoover, Holly; Thuerauf, Donna J.; Glembotski, Christopher C.

doi:10.1161/01.res.0000052989.83995.a5

Cited by 140 publications

(130 citation statements)

References 41 publications

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“…Since aB-crystallin and FAK may influence the viability and the hypertrophic response of cardiomyocytes to stress 13,19 , NRVMs depleted of aB-crystallin were analysed after prolonged (12 h) mechanical stress. Non-stretched cardiomyocytes depleted of aB-crystallin showed a minor reduction in cell viability, but no change in cell morphology (Fig.…”

Section: Structural Basis Of the Fak-cterm-ab-crystallin Interactionmentioning

confidence: 99%

“…It is therefore not surprising that inherited defects and the experimental gene targeting of aB-crystallin result in protein deposition diseases of cardiac and skeletal muscles 10,11 . However, in addition to its primordial duty as a molecular chaperone, aB-crystallin plays critical roles in essential cellular processes, including differentiation and survival 12,13 , suggesting that it may function as a key component in signal transduction networks. Accordingly, aB-crystallin is known to bind and modulate the activity of several signalling proteins in their native state, including Bax, Bcl-2 and p53 (refs 14,15); the knowledge of this regulation is rapidly emerging.…”

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confidence: 99%

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αB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes

Pereira¹,

Santos²,

Gonçalves³

et al. 2014

Nat Commun

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Focal adhesion kinase (FAK) contributes to cellular homeostasis under stress conditions. Here we show that aB-crystallin interacts with and confers protection to FAK against calpainmediated proteolysis in cardiomyocytes. A hydrophobic patch mapped between helices 1 and 4 of the FAK FAT domain was found to bind to the b4-b8 groove of aB-crystallin. Such an interaction requires FAK tyrosine 925 and is enhanced following its phosphorylation by Src, which occurs upon FAK stimulation. aB-crystallin silencing results in calpain-dependent FAK depletion and in the increased apoptosis of cardiomyocytes in response to mechanical stress. FAK overexpression protects cardiomyocytes depleted of aB-crystallin against the stretch-induced apoptosis. Consistently, load-induced apoptosis is blunted in the hearts from cardiac-specific FAK transgenic mice transiently depleted of aB-crystallin by RNA interference. These studies define a role for aB-crystallin in controlling FAK function and cardiomyocyte survival through the prevention of calpain-mediated degradation of FAK.

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Section: Structural Basis Of the Fak-cterm-ab-crystallin Interactionmentioning

confidence: 99%

mentioning

confidence: 99%

αB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes

Pereira¹,

Santos²,

Gonçalves³

et al. 2014

Nat Commun

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“…Hyperosmotic stress induces cell apoptosis by activating JNK and p38 signaling pathways in various cell types (Qin et al, 1997;Bilney and Murray, 1998;Malek et al, 1998;Hoover et al, 2000;Lu et al, 2000;Morrison et al, 2003;Reinehr et al, 2003). In corneal epithelial cells, the effect of hyperosmotic stress on apoptosis is characterized by measuring cell viability and activations of JNK and p38 signaling pathways.…”

Section: Independence Of Hypertonic Stress-induced Jnk Activation On mentioning

confidence: 99%

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

2006

Progress in Retinal and Eye Research

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One of the functional roles of the corneal epithelial layer is to protect the cornea, lens and other underlying ocular structures from damages caused by environmental insults. It is important for corneal epithelial cells to maintain this function by undergoing continuous renewal through a dynamic process of wound healing. Previous studies in corneal epithelial cells have provided substantial evidence showing that environmental insults, such as ultraviolet (UV) irradiation and other biohazards, can induce stress-related cellular responses resulting in apoptosis and thus interrupt the dynamic process of wound healing. We found that UV irradiation-induced apoptotic effects in corneal epithelial cells are started by the hyperactivation of K + channels in the cell membrane resulting in a fast loss of intracellular K + ions. Recent studies provide further evidence indicating that these complex responses in corneal epithelial cells are resulted from the activation of stressrelated signaling pathways mediated by K + channel activity. The effect of UV irradiation on corneal epithelial cell fate shares common signaling mechanisms involving the activation of intracellular responses that are often activated by the stimulation of various cytokines. One piece of evidence for making this distinction is that at early times UV irradiation activates a Kv3.4 channel in corneal epithelial cells to elicit activation of c-Jun N-terminal kinase cascades and p53 activation leading to cell cycle arrest and apoptosis. The hypothetic model is that UV-induced potassium channel hyperactivity as an early event initiates fast cell shrinkages due to the loss of intracellular potassium, resulting in the activation of scaffolding protein kinases and cytoskeleton reorganizations. This review article presents important control mechanisms that determine Kv channel activity-mediated cellular responses in corneal epithelial cells, involving activation of stress-induced signaling pathways, arrests of cell cycle progression and/or induction of apoptosis.

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“…It has been proposed that αB-crystallin and HSP25/27 mediate cardioprotection by binding to proteins of the cytoskeleton and the myofilaments to attenuate ischemic injury (Eaton et al 2000). Overexpression of αB-crystallin has been shown to attenuate ischemic injury in cultured cardiac myocytes (Bluhm et al 1998) and in transgenic mice (Ray et al 2001), and the cytoprotection appears dependent on the phosphorylation of the Ser-59 residue, which in turn is dependent on MAPKAPK-2 (Kato et al 1998) and p38 MAPK (Morrison et al 2003).…”

Section: Introductionmentioning

confidence: 99%

MAPKAPK-2 modulates p38-MAPK localization and small heat shock protein phosphorylation but does not mediate the injury associated with p38-MAPK activation during myocardial ischemia

Gorog¹,

Jabr²,

Tanno³

et al. 2009

Cell Stress and Chaperones

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MAPKAPK-2 (MK2) is a protein kinase activated downstream of p38-MAPK which phosphorylates the small heat shock proteins HSP27 and αB crystallin and modulates p38-MAPK cellular distribution. p38-MAPK activation is thought to contribute to myocardial ischemic injury; therefore, we investigated MK2 effects on ischemic injury and p38 cellular localization using MK2-deficient mice (KO). Immunoblotting of extracts from Langendorffperfused hearts subjected to aerobic perfusion or global ischemia or reperfusion showed that the total and phosphorylated p38 levels were significantly lower in MK2 −/− compared to MK2 +/+ hearts at baseline, but the ratio of phosphorylated/total p38 was similar. These results were confirmed by cellular fractionation and immunoblotting for both cytosolic and nuclear compartments. Furthermore, HSP27 and αB crsytallin phosphorylation were reduced to baseline in MK2 −/− hearts. On semiquantitative immunofluorescence laser confocal microscopy of hearts during aerobic perfusion, the mean total p38 fluorescence was significantly higher in the nuclear compared to extranuclear (cytoplasmic, sarcomeric, and sarcolemmal compartments) in MK2 +/+ hearts. However, although the increase in phosphorylated p38 fluorescence intensity in all compartments following ischemia in MK2 +/+ hearts was lost in MK2 −/− hearts, it was basally elevated in nuclei of MK2 −/− hearts and was similar to that seen during ischemia in MK2 +/+ hearts. Despite these differences, similar infarct volumes were recorded in wild-type MK2 +/+ and MK2 −/− hearts, which were decreased by the p38 inhibitor SB203580 (1 μM) in both genotypes. In conclusion, p38 MAPKinduced myocardial ischemic injury is not modulated by MK2. However, the absence of MK2 perturbs the cellular distribution of p38. The preserved nuclear distribution of active p38 MAPK in MK2 −/− hearts and the conserved

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Mimicking Phosphorylation of αB-Crystallin on Serine-59 Is Necessary and Sufficient to Provide Maximal Protection of Cardiac Myocytes From Apoptosis

Cited by 140 publications

References 41 publications

αB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes

αB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

MAPKAPK-2 modulates p38-MAPK localization and small heat shock protein phosphorylation but does not mediate the injury associated with p38-MAPK activation during myocardial ischemia

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