Calpain interacts with class IA phosphoinositide 3-kinases regulating their stability and signaling activity

Beltran, Luisa; Chaussade, Claire; Vanhaesebroeck, Bart; Cutillas, Pedro R.

doi:10.1073/pnas.1107692108

Cited by 38 publications

(24 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently, it has been suggested that calpain is capable of partially modulating cellular proliferative signals dependent on the PI3K/mTOR signaling pathway [22]. In cases of cardiac disease, where there is no effective process of neo-vascularization, repair and tissue regeneration may be limited or may not occur.…”

Section: Discussionmentioning

confidence: 99%

“…Recent, evidence indicates that calpain plays a dual role in protein metabolism through the concomitant activation of proteasome-dependent proteolysis and inhibition of the PI3K/Akt protein synthesis pathway [22]. Furthermore, mTOR inhibition mediated by calpain could potentially reduce the overall rates of protein synthesis, reducing the available translational machinery required for the maintenance of the protein synthesis levels [15].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, mTOR inhibition mediated by calpain could potentially reduce the overall rates of protein synthesis, reducing the available translational machinery required for the maintenance of the protein synthesis levels [15]. Although a regulatory role of the PI3K/Akt/mTOR pathway, partly dependent of calpain, has been demonstrated in cell growth and survival during serum deprivation [22], little has been elucidated about how the PI3K/mTOR signaling pathway is modulated by calpain during cardiac dysfunction.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition

et al. 2016

View full text Add to dashboard Cite

Cardiac dysfunction caused by the impairment of myocardial contractility has been recognized as an important factor contributing to the high mortality in sepsis. Calpain activation in the heart takes place in response to increased intracellular calcium influx resulting in proteolysis of structural and contractile proteins with subsequent myocardial dysfunction. The purpose of the present study was to test the hypothesis that increased levels of calpain in the septic heart leads to disruption of structural and contractile proteins and that administration of calpain inhibitor-1 (N-acetyl-leucinyl-leucinyl-norleucinal (ALLN)) after sepsis induced by cecal ligation and puncture prevents cardiac protein degradation. We also tested the hypothesis that calpain plays a role in the modulation of protein synthesis/degradation through the activation of proteasome-dependent proteolysis and inhibition of the mTOR pathway. Severe sepsis significantly increased heart calpain-1 levels and promoted ubiquitin and Pa28β over-expression with a reduction in the mTOR levels. In addition, sepsis reduced the expression of structural proteins dystrophin and β-dystroglycan as well as the contractile proteins actin and myosin. ALLN administration prevented sepsis-induced increases in calpain and ubiquitin levels in the heart, which resulted in decreased of structural and contractile proteins degradation and basal mTOR expression levels were re-established. Our results support the concept that increased calpain concentrations may be part of an important mechanism of sepsis-induced cardiac muscle proteolysis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Indeed, the regulation of proteolytic activity is complex and involves the association of calpain with a regulatory subunit, the endogenous inhibitor calpastatin, 4 other interacting proteins, 5 and binding to phospholipids. 6,7 Genetic deletion of m-calpain results in embryonic lethality, 8,9 but -calpain Ϫ/Ϫ mice are viable and demonstrate attenuated aggregation and clot retraction but normal bleeding times. 10 Mechanistically, the latter effects were attributed to the tyrosine dephosphorylation of platelet proteins because -calpain Ϫ/Ϫ platelets exhibited high levels of tyrosine phosphatase 1B protein and activity.…”

Section: Introductionmentioning

confidence: 99%

Calpain inhibition stabilizes the platelet proteome and reactivity in diabetes

Randriamboavonjy

Isaak

Elgheznawy

et al. 2012

Blood

View full text Add to dashboard Cite

Platelets from patients with diabetes are hyperreactive and demonstrate increased adhesiveness, aggregation, degranulation, and thrombus formation, processes that contribute to the accelerated development of vascular disease. Part of the problem seems to be dysregulated platelet Ca 2؉ signaling and the activation of calpains, which are Ca 2؉ -activated proteases that result in the limited proteolysis of substrate proteins and subsequent alterations in signaling. In the present study, we report that the activation of -and m-calpain in patients with type 2 diabetes has profound effects on the platelet proteome and have identified septin-5 and the integrin-linked kinase (ILK) as novel calpain substrates. The calpain-dependent cleavage of septin-5 disturbed its association with syntaxin-4 and promoted the secretion of ␣-granule contents, including TGF-␤ and CCL5. Calpain was also released by platelets and cleaved CCL5 to generate a variant with enhanced activity. Calpain activation also disrupted the ILK-PINCH-Parvin complex and altered platelet adhesion and spreading. In diabetic mice, calpain inhibition reversed the effects of diabetes on platelet protein cleavage, decreased circulating CCL5 levels, reduced plateletleukocyte aggregate formation, and improved platelet function. The results of the present study indicate that diabetesinduced platelet dysfunction is mediated largely by calpain activation and suggest that calpain inhibition may be an effective way of preserving platelet function and eventually decelerating atherothrombosis development. (Blood. 2012;120(2): 415-423) IntroductionCalpains are Ca 2ϩ -regulated cysteine proteases that are responsible for the limited proteolysis of target proteins, resulting in their modification (eg, activation, inhibition, or altered sensitivity to intracellular signals) rather than in their degradation. 1 In contrast to promiscuous degradative proteases, calpains cleave a relatively restricted set of protein substrates and use complex substrate recognition mechanisms involving primary and secondary structural features of target proteins to alter protein function and cellular signaling. 2 Platelets express -calpain (calpain 1) and m-calpain (calpain 2); named for the micro-and millimolar Ca 2ϩ concentrations, respectively, that are required to activate them in vitro. 3 Although Ca 2ϩ is the main regulator of calpain activity, protease activation does not simply occur in response to any stimuli that increases platelet Ca 2ϩ . Indeed, the regulation of proteolytic activity is complex and involves the association of calpain with a regulatory subunit, the endogenous inhibitor calpastatin, 4 other interacting proteins, 5 and binding to phospholipids. 6,7 Genetic deletion of m-calpain results in embryonic lethality, 8,9 but -calpain Ϫ/Ϫ mice are viable and demonstrate attenuated aggregation and clot retraction but normal bleeding times. 10 Mechanistically, the latter effects were attributed to the tyrosine dephosphorylation of platelet proteins because -calpain Ϫ/Ϫ platelets exh...

show abstract

“…However, previous studies have shown that calpain may inhibit insulin signaling [50]–[53]. We also examined how calpain inhibition would affect the inhibitory effect of DEX on D6, when no activation of μ-calpain was observed upon DEX treatment (D6, lane 2, Fig.…”

Section: Resultsmentioning

confidence: 99%

Tau Phosphorylation and μ-Calpain Activation Mediate the Dexamethasone-Induced Inhibition on the Insulin-Stimulated Akt Phosphorylation

Liu

Sun

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

Evidence has suggested that insulin resistance (IR) or high levels of glucocorticoids (GCs) may be linked with the pathogenesis and/or progression of Alzheimer's disease (AD). Although studies have shown that a high level of GCs results in IR, little is known about the molecular details that link GCs and IR in the context of AD. Abnormal phosphorylation of tau and activation of μ-calpain are two key events in the pathology of AD. Importantly, these two events are also related with GCs and IR. We therefore speculate that tau phosphorylation and μ-calpain activation may mediate the GCs-induced IR. Akt phosphorylation at Ser-473 (pAkt) is commonly used as a marker for assessing IR. We employed two cell lines, wild-type HEK293 cells and HEK293 cells stably expressing the longest human tau isoform (tau-441; HEK293/tau441 cells). We examined whether DEX, a synthetic GCs, induces tau phosphorylation and μ-calpain activation. If so, we examined whether the DEX-induced tau phosphorylation and μ-calpain activation mediate the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation. The results showed that DEX increased tau phosphorylation and induced tau-mediated μ-calpain activation. Furthermore, pre-treatment with LiCl prevented the effects of DEX on tau phosphorylation and μ-calpain activation. Finally, both LiCl pre-treatment and calpain inhibition prevented the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation. In conclusion, our study suggests that the tau phosphorylation and μ-calpain activation mediate the DEX-induced inhibition on the insulin-stimulated Akt phosphorylation.

show abstract

Calpain interacts with class IA phosphoinositide 3-kinases regulating their stability and signaling activity

Cited by 38 publications

References 49 publications

Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition

Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition

Calpain inhibition stabilizes the platelet proteome and reactivity in diabetes

Tau Phosphorylation and μ-Calpain Activation Mediate the Dexamethasone-Induced Inhibition on the Insulin-Stimulated Akt Phosphorylation

Contact Info

Product

Resources

About