Calpain‐dependent proteolysis of NF2 protein: Involvement in schwannomas and meningiomas

Kimura, Yuri; Saya, Hideyuki; Nakao, Mitsuyoshi

doi:10.1046/j.1440-1789.2000.00326.x

Cited by 33 publications

(19 citation statements)

References 55 publications

(85 reference statements)

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“…Calpain is implicated in numerous pathological conditions including Alzheimer's disease; demyelination events of multiple sclerosis; neuronal damage after spinal cord injury and hypoxic/ ischemic injury to brain, kidney and heart organs; and tumor development and invasion (49)(50)(51)(52)(53). Thus, the elucidation of the mechanisms by which calpain activity is regulated is of interest for the development of therapeutics for a wide range of pathological states.…”

Section: Discussionmentioning

confidence: 99%

Acute-Phase Protein α1-Antitrypsin Inhibits Neutrophil Calpain I and Induces Random Migration

Al-Omari

Korenbaum

Ballmaier

et al. 2011

Mol Med

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A rapid recruitment of neutrophils to sites of injury or infection is a hallmark of the inflammatory response and is required for effective host defense against pathogenic stimuli. However, neutrophil-mediated inflammation can also lead to chronic tissue destruction; therefore, a better understanding of the mechanisms underlying neutrophil influx and activation is of critical importance. We have previously shown that the acute phase protein α1-antitrypsin (AAT) inhibits neutrophil chemotaxis. In this study, we examine mechanisms related to the effect of AAT on neutrophil responses. We report a previously unknown function of AAT to inactivate calpain I (μ-calpain) and to induce a rapid cell polarization and random migration. These effects of AAT coincided with a transient rise in intracellular calcium, increase in intracellular lipids, activation of the Rho GTPases, Rac1 and Cdc42, and extracellular signal-regulated kinase (ERK1/2). Furthermore, AAT caused a significant inhibition of nonstimulated as well as formyl-metleu-phe (fMLP)-stimulated neutrophil adhesion to fibronectin, strongly inhibited lipopolysaccharide-induced IL-8 release and slightly delayed neutrophil apoptosis. The results presented here broaden our understanding of the regulation of calpain-related neutrophil functional activities, and provide the impetus for new studies to define the role of AAT and other acute phase proteins in health and disease.

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Section: Discussionmentioning

confidence: 99%

Acute-Phase Protein α1-Antitrypsin Inhibits Neutrophil Calpain I and Induces Random Migration

Al-Omari

Korenbaum

Ballmaier

et al. 2011

Mol Med

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“…10). Two separate in vivo studies suggest a role for calpain activity in the metastases of renal cell carcinoma and an association with the development of some schwannomas and meningiomas (10,32). Thus, manipulation of the calpain-calpastatin proteolytic system may represent a useful …”

Section: Discussionmentioning

confidence: 99%

“…Previous studies indicate that calpain can regulate cell cycle progression at distinct points through modulating the protein levels of several cell cycle regulators, such as the tumor suppressor proteins p53, p107, and NF2 (26,32,34). In addition, cyclin D1 and the cyclindependent kinase (cdk) inhibitor p27 kip1 are both calpain substrates and so may represent other pathways by which calpain can regulate cell cycle progression (15,49).…”

mentioning

confidence: 99%

v-Src-Induced Modulation of the Calpain-Calpastatin Proteolytic System Regulates Transformation

Carragher

Westhoff

Riley

et al. 2002

Molecular and Cellular Biology

105

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v-Src-induced oncogenic transformation is characterized by alterations in cell morphology, adhesion, motility, survival, and proliferation. To further elucidate some of the signaling pathways downstream of v-Src that are responsible for the transformed cell phenotype, we have investigated the role that the calpain-calpastatin proteolytic system plays during oncogenic transformation induced by v-Src. We recently reported that v-Srcinduced transformation of chicken embryo fibroblasts is accompanied by calpain-mediated proteolytic cleavage of the focal adhesion kinase (FAK) and disassembly of the focal adhesion complex. In this study we have characterized a positive feedback loop whereby activation of v-Src increases protein synthesis of calpain II, resulting in degradation of its endogenous inhibitor calpastatin. Reconstitution of calpastatin levels by overexpression of exogenous calpastatin suppresses proteolytic cleavage of FAK, morphological transformation, and anchorage-independent growth. Furthermore, calpastatin overexpression represses progression of v-Src-transformed cells through the G 1 stage of the cell cycle, which correlates with decreased pRb phosphorylation and decreased levels of cyclins A and D and cyclin-dependent kinase 2. Calpain 4 knockout fibroblasts also exhibit impaired v-Src-induced morphological transformation and anchorage-independent growth. Thus, modulation of the calpain-calpastatin proteolytic system plays an important role in focal adhesion disassembly, morphological transformation, and cell cycle progression during v-Src-induced cell transformation.Oncogenic transformation of cells by v-Src is associated with deregulated growth control, cytoskeketal disassembly, and loss of integrin-linked focal adhesion structures (17,20,27,31). Such alterations contribute to the highly mitogenic and motile phenotype that characterizes v-Src transformation. The precise mechanisms by which v-Src promotes cell transformation remain poorly understood. Previous studies, however, indicate that v-Src-induced morphological transformation occurs by mechanisms independent of gene expression (8,22), implicating Src kinase activity or other posttranscriptional mechanisms as key mediators of v-Src-induced transformation. Calpainmediated proteolysis represents a major pathway of posttranslational modification of cellular proteins and has been implicated in diverse cellular processes ranging from apoptosis to cell migration and cell cycle progression (12,25,43,45,49,57). We have previously demonstrated that calpain-mediated proteolytic cleavage of the focal adhesion kinase (FAK) and focal adhesion disassembly accompany v-Src-induced morphological transformation. Calpain-mediated disassembly of focal adhesions results in a reduction in the strength of adhesion that transformed cells have to their culture substrate, thereby promoting cell motility (12).The calpains represent a highly conserved family of nonlysosomal calcium-dependent cysteine proteases comprising two ubiquitously expressed isoforms, -calpain (cal...

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“…For instance, increased calpain activity has been detected in breast cancer tissues (Shiba et al, 1996), and in human renal cell carcinomas significantly higher levels of µCp expression were found in tumors metastazing to peripheral lymph nodes compared to tumors that have not metastasized (Braun et al, 1999). Interestingly, calpain-mediated proteolysis of the tumor suppressor protein, neurofibromatosis type 2, is associated with the development of schwannomas and meningiomas (Kimura et al, 2000). Finally, elevated calpain activity in chronic lymphocytic leukemic cells (Witkowski et al, 2002) and involvement of calpains in differentiation of leukemic cells have been reported as well (Deshpande et al, 1995).…”

mentioning

confidence: 99%

The Calpastatin-Derived Calpain Inhibitor CP1B Reduces mRNA Expression of Matrix Metalloproteinase-2 and -9 and Invasion by Leukemic THP-1 Cells

Popp¹,

Heidinger²,

Ruiz-Heinrich³

et al. 2003

Biological Chemistry

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Calpain‐dependent proteolysis of NF2 protein: Involvement in schwannomas and meningiomas

Cited by 33 publications

References 55 publications

Acute-Phase Protein α1-Antitrypsin Inhibits Neutrophil Calpain I and Induces Random Migration

Acute-Phase Protein α1-Antitrypsin Inhibits Neutrophil Calpain I and Induces Random Migration

v-Src-Induced Modulation of the Calpain-Calpastatin Proteolytic System Regulates Transformation

The Calpastatin-Derived Calpain Inhibitor CP1B Reduces mRNA Expression of Matrix Metalloproteinase-2 and -9 and Invasion by Leukemic THP-1 Cells

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