Differential distribution of calpain in human lymphoid cells

Deshpande, Rajendra V.; Goust, Jean‐Michel; Banik, Naren L.

doi:10.1007/bf00966771

Cited by 13 publications

(6 citation statements)

References 42 publications

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“…In contrast, the supernatant of nonactivated THP-1 cells did not degrade myelin, possibly due to a much lower amount of calpain secreted in the extracellular medium, compared with that of activated cells. This finding correlates well with our previous observation that degradation of MBP by calpain is concentration-dependent (Deshpande et al, 1993).…”

Section: Discussionsupporting

confidence: 93%

“…A large amount (50%) of MBP can be degraded in 1 hr by both isoforms, suggesting that calpains have a strong potential to contribute effectively to demyelination. Increasing amounts of calpain have degraded MBP to greater extents (Deshpande et al, 1993), suggesting that calpain, if produced and secreted locally in large amounts by inflammatory cells in the nervous tissue, may cause degradation of myelin proteins such as that seen in MS or EAE. Degradation of MBP by calpain from other sources (Sato et al, 1982;Chakrabarti and Banik, 1988;Yanagisawa et al, 1988) has been previously demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…If calpain participates in lesion development in MS and EAE (Smith, 1977), it may originate from the activated mononuclear cells infiltrating the diseased CNS and/or from resident cells such as astrocytes and microglia exposed to stimulatory cytokines. In previous studies, we have shown that calpain is present in lymphoid cell lines in a form in which it can degrade MBP (Deshpande et al, 1993). Although calpains are considered predominantly, if not exclusively, intracellular, we have also observed (Deshpande et al, 1992) that activation of T-and B-cell lines by agents mimicking their activation via antigen-receptors not only induces a several-fold increase in calpain mRNA expression and protein production, but also leads to the appearance of large amounts of calpain in the extracellular medium.…”

Section: Introductionmentioning

confidence: 99%

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Calpain secreted by activated human lymphoid cells degrades myelin

Deshpande

Goust

Hogan

et al. 1995

J of Neuroscience Research

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Calpain secreted by lymphoid (MOLT-3, M.R.) or monocytic (U-937, THP-1) cell lines activated with PMA and A23187 degraded myelin antigens. The degradative effect of enzymes released in the extracellular medium was tested on purified myelin basic protein and rat central nervous system myelin in vitro. The extent of protein degradation was determined by SDS-PAGE and densitometric analysis. Various proteinase inhibitors were used to determine to what extent protein degradation was mediated by calpain and/or other enzymes. Lysosomal and serine proteinase inhibitors inhibited 20-40% of the myelin-degradative activity found in the incubation media of cell lines, whereas the calcium chelator (EGTA), the calpain-specific inhibitor (calpastatin), and a monoclonal antibody to m calpain blocked myelin degradation by 60-80%. Since breakdown products of MBP generated by calpain may include fragments with antigenic epitopes, this enzyme may play an important role in the initiation of immune-mediated demyelination.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Calpain secreted by activated human lymphoid cells degrades myelin

Deshpande

Goust

Hogan

et al. 1995

J of Neuroscience Research

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“…Furthermore, stimulation of T cells with these substances causes calpaininduced proteolytic cleavage of PTP-1B, resulting in a 42-kDa enzymatically active form of the phosphatase as a result of C-terminal truncation. Interestingly, PTP-1B can be cleaved by calpain I and calpain II, both of which are present in T cells (37). PTP-1B normally associates with the ER membrane via a C terminus-targeting sequence, whereas the catalytic domain is located near the N terminus (29,30).…”

Section: Discussionmentioning

confidence: 99%

Calcium-dependent Signaling Pathways in T Cells

Rock

Brooks

Roszman

1997

Journal of Biological Chemistry

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Engagement of ␤1 integrin receptors initiates an increase in intracellular calcium concentrations in T cells, potentially affecting calcium-sensitive signaling pathways. The calcium-activated cysteine protease, calpain, regulates a variety of cell functions by calcium-dependent limited proteolysis. To investigate the function of calpain in T cells, we sought to determine the role of this protease in calcium-dependent signaling events. Subsequent to elevations in intracellular calcium concentrations induced by ionomycin or adherence to fibronectin, calpain activity translocated to the cytoskeletal/membrane fraction of T cells. In addition, stimulation of T cells with these agents initiated the proteolytic cleavage of protein tyrosine phosphatase 1B by calpain. Enzymatic cleavage of protein tyrosine phosphatase 1B occurs near the endoplasmic reticulum-targeting sequence and results in the generation of an enzymatically active form of the phosphatase. Furthermore, we show that both the native and the cleaved forms of protein tyrosine phosphatase 1B interact with p130Cas in T cells. This interaction may serve to relocate protein tyrosine phosphatase 1B to sites of focal contact resulting in potential interactions with substrates previously inaccessible to the endoplasmic reticulum-associated phosphatase. Thus, we describe a novel calcium-dependent signaling pathway in T cells that may mediate signals generated by ␤1 integrin adherence to the extracellular matrix.Calpain (calcium-activated cysteine protease; EC 3.4.22.17) is ubiquitously expressed in mammalian cells, yet its precise physiologic function in T cells remains to be determined. The majority of calpain is localized in the cytosol of cells (1-4). However, raising intracellular calcium concentrations ([Ca 2ϩ ] i ) 1 in cells induces calpain translocation to the plasma membrane, the cytoskeleton, and points of attachment between cells and the extracellular matrix (ECM) (5-9). Furthermore, interactions between integrins and ECM proteins in some cell types, induces the translocation and activation of calpain in response to elevated [Ca 2ϩ ] i (5, 10 -12). Calpain can induce the proteolytic modification of proteins associated with multiple signaling cascades, such as protein kinase C, phospholipase C, pp60Src , and focal adhesion kinase (13-16) as well as the limited proteolysis of cytoskeletal proteins including talin, actinbinding protein, and paxillin (17-19). Thus, calpain is implicated in cytoskeletal reorganization as well as signal transduction pathways in response to elevations in [Ca 2ϩ ] i . This suggests that calpain has a crucial role in integrin-induced alterations in cellular physiology and function. Interaction of integrins with their ligands activates cellular signaling pathways and reorganization of the cytoskeletal system (20 -24). An increase in [Ca 2ϩ ] i represents one second messenger that is quantitatively altered as a consequence of these interactions. This would further suggest the possibility that calpain is activated b...

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“…The role of calpain was examined since all major myelin proteins, including myelin basic protein (MBP) and axonal neurofilament protein (NFP), are substrates of calpain [213, 214]. Activated T-cells also have increased intracellular calcium [215] and express and secrete calpain [216-218]. Using an animal model of MS, experimental allergic encephalitis (EAE), calpain expression was increased twofold over control with decreased levels of myelin associated glycoprotein and NFP [219].…”

Section: Multiple Sclerosismentioning

confidence: 99%

Calpain-Mediated Signaling Mechanisms in Neuronal Injury and Neurodegeneration

2008

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Calpain is a ubiquitous calcium-sensitive protease that is essential for normal physiologic neuronal function. However, alterations in calcium homeostasis lead to persistent, pathologic activation of calpain in a number of neurodegenerative diseases. Pathologic activation of calpain results in the cleavage of a number of neuronal substrates that negatively affect neuronal structure and function, leading to inhibition of essential neuronal survival mechanisms. In this review, we examine the mechanistic underpinnings of calcium dysregulation resulting in calpain activation in the acute neurodegenerative diseases such as cerebral ischemia and in the chronic neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, prionrelated encephalopathy, and amylotrophic lateral sclerosis. The premise of this paper is that analysis of the signaling and transcriptional consequences of calpain-mediated cleavage of its various substrates for any neurodegenerative disease can be extrapolated to all of the neurodegenerative diseases vulnerable to calcium dysregulation.

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Differential distribution of calpain in human lymphoid cells

Cited by 13 publications

References 42 publications

Calpain secreted by activated human lymphoid cells degrades myelin

Calpain secreted by activated human lymphoid cells degrades myelin

Calcium-dependent Signaling Pathways in T Cells

Calpain-Mediated Signaling Mechanisms in Neuronal Injury and Neurodegeneration

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