Calpastatin, an endogenous calpain-inhibitor protein, regulates the cleavage of the Cdk5 activator p35 to p25

Sato, Ko; Minegishi, Seiji; Takano, Jiro; Plattner, Florian; Saito, Taro; Asada, Akiko; Kawahara, Hiroyuki; Iwata, Nobuhisa; Saido, Takaomi C.; Hisanaga, Shin Ichi

doi:10.1111/j.1471-4159.2011.07222.x

Cited by 31 publications

(20 citation statements)

References 49 publications

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“…In agreement with this finding, calpains -particularly m-and m-calpain -are abnormally activated in AD (Saito et al, 1993). Similarly, calpastatin, an endogenous inhibitor of calpains, is substantially decreased in AD (Nixon, 2003), which could lead to deregulation of Cdk5 through increased formation of p25 (Sato et al, 2011). Although a few in vitro studies have shown that the complex between Cdk5 and p25 displays a higher activity than that between Cdk5 and p35, other studies have reported comparable activities (Peterson et al, 2010).…”

Section: Introductionsupporting

confidence: 57%

Cdk5 activity in the brain – multiple paths of regulation

Shah

Lahiri

2014

Journal of Cell Science

167

126

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Cyclin dependent kinase-5 (Cdk5), a family member of the cyclindependent kinases, plays a pivotal role in the central nervous system. During embryogenesis, Cdk5 is indispensable for brain development and, in the adult brain, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation. However, Cdk5 activity becomes deregulated in several neurological disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, which leads to neurotoxicity. Therefore, precise control over Cdk5 activity is essential for its physiological functions. This Commentary covers the various mechanisms of Cdk5 regulation, including several recently identified protein activators and inhibitors of Cdk5 that control its activity in normal and diseased brains. We also discuss the autoregulatory activity of Cdk5 and its regulation at the transcriptional, post-transcriptional and post-translational levels. We finally highlight physiological and pathological roles of Cdk5 in the brain. Specific modulation of these protein regulators is expected to provide alternative strategies for the development of effective therapeutic interventions that are triggered by deregulation of Cdk5.

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Section: Introductionsupporting

confidence: 57%

Cdk5 activity in the brain – multiple paths of regulation

Shah

Lahiri

2014

Journal of Cell Science

167

126

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“…The cleavage of TDP-43 was induced by incubation of the extracts in the presence of 5 mM CaCl 2 at 30 1C (ref. 58). The SDS sample buffer was added to stop the reaction.…”

Section: Constructionmentioning

confidence: 99%

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

et al. 2012

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Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 colocalize in the motor neurons of amyotrophic lateral sclerosis patients, but how they are linked is not clear. Here we demonstrate that activation of calpain, a Ca 2 þ -dependent cysteine protease, by upregulation of Ca 2 þ -permeable AMPA receptors generates carboxyterminal-cleaved TDP-43 fragments and causes mislocalization of TDP-43 in the motor neurons expressing glutamine/arginine site-unedited GluA2 of conditional ADAR2 knockout (AR2) mice that mimic the amyotrophic lateral sclerosis pathology. These abnormalities are inhibited in the AR2res mice that express Ca 2 þ -impermeable AMPA receptors in the absence of ADAR2 and in the calpastatin transgenic mice, but are exaggerated in the calpastatin knockout mice. Additional demonstration of calpain-dependent TDP43 fragments in the spinal cord and brain of amyotrophic lateral sclerosis patients, and high vulnerability of amyotrophic lateral sclerosis-linked mutant TDP43 to cleavage by calpain support the crucial role of the calpain-dependent cleavage of TDP43 in the amyotrophic lateral sclerosis pathology.

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“…−3, −9) are tissue-specific. 5 Activated calpain by calcium causes damage to cells by selectively degrading intracellular proteins, including signaling proteins (eg, cyclin-dependent kinase, protein kinase C) 6, 7 , cytoskeletal proteins (eg, talin, spectrin) 8, 9 , and transcription factors (eg, c-Jun, IkB). 10–12 Calpains play a critical role in cellular apoptosis through the activation of both caspase-dependent and caspase-independent pathways.…”

Section: Introductionmentioning

confidence: 99%

Leukocyte Calpain Deficiency Reduces Angiotensin II–Induced Inflammation and Atherosclerosis But Not Abdominal Aortic Aneurysms in Mice

Howatt

Balakrishnan

Moorleghen

et al. 2016

ATVB

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Objective Angiotensin II (AngII)-infusion profoundly increases activity of calpains, calcium-dependent neutral cysteine proteases, in mice. Pharmacological inhibition of calpains attenuates AngII-induced aortic medial macrophage accumulation, atherosclerosis, and abdominal aortic aneurysm in mice. However, the precise functional contribution of leukocyte-derived calpains in AngII-induced vascular pathologies has not been determined. The purpose of this study was to determine whether calpains expressed in bone marrow (BM)-derived cells contribute to AngII-induced atherosclerosis and aortic aneurysms in hypercholesterolemic mice. Approach and Results To study whether leukocyte calpains contributed to AngII-induced aortic pathologies, irradiated male LDL receptor −/− mice were repopulated with BM-derived cells that were either wild-type(WT) or overexpressed calpastatin (CAST), the endogenous inhibitor of calpains. Mice were fed a fat-enriched diet and infused with AngII (1,000 ng/kg/min) for 4 weeks. Overexpression of CAST in BM-derived cells significantly attenuated AngII-induced atherosclerotic lesion formation in aortic arches, but had no effect on aneurysm formation. Using either BM-derived cells from calpain-1 deficient mice or mice with leukocyte-specific calpain-2 deficiency generated using cre-loxP recombination technology, further studies demonstrated that independent deficiency of either calpain-1 or -2 in leukocytes modestly attenuated AngII-induced atherosclerosis. CAST overexpression significantly attenuated AngII-induced inflammatory responses in macrophages and spleen. Furthermore, calpain inhibition suppressed migration and adhesion of macrophages to endothelial cells in vitro. Calpain inhibition also significantly decreased hypercholesterolemia-induced atherosclerosis in the absence of AngII. Conclusions The present study demonstrates a pivotal role for BM-derived calpains in mediating AngII-induced atherosclerosis by influencing macrophage function.

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Calpastatin, an endogenous calpain-inhibitor protein, regulates the cleavage of the Cdk5 activator p35 to p25

Cited by 31 publications

References 49 publications

Cdk5 activity in the brain – multiple paths of regulation

Cdk5 activity in the brain – multiple paths of regulation

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

Leukocyte Calpain Deficiency Reduces Angiotensin II–Induced Inflammation and Atherosclerosis But Not Abdominal Aortic Aneurysms in Mice

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