Changes in intracellular localization of calpastatin during calpain activation

Tullio, Roberta De; Passalacqua, Mario; Averna, Monica; Salamino, Franca; Melloni, Edon; Pontremoli, S.

doi:10.1042/bj3430467

Cited by 61 publications

(65 citation statements)

References 15 publications

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“…sufficient to activate calpains. Furthermore, structural and biochemical data indicate that calpastatin might bind preferentially to calcium-activated calpains (Barnoy et al, 1999;Tullio et al, 1999), suggesting that this is an attenuation mechanism rather than a preventive one.…”

Section: Fig 2 (A)mentioning

confidence: 99%

Regulating cell migration: calpains make the cut

Franco

Huttenlocher

2005

Journal of Cell Science

437

406

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The calpain family of proteases has been implicated in cellular processes such as apoptosis, proliferation and cell migration. Calpains are involved in several key aspects of migration, including: adhesion and spreading; detachment of the rear; integrin- and growth-factor-mediated signaling; and membrane protrusion. Our understanding of how calpains are activated and regulated during cell migration has increased as studies have identified roles for calcium and phospholipid binding, autolysis, phosphorylation and inhibition by calpastatin in the modulation of calpain activity. Knockout and knockdown approaches have also contributed significantly to our knowledge of calpain biology, particularly with respect to the specific functions of different calpain isoforms. The mechanisms by which calpain-mediated proteolysis of individual substrates contributes to cell motility have begun to be addressed, and these efforts have revealed roles for proteolysis of specific substrates in integrin activation, adhesion complex turnover and membrane protrusion dynamics. Understanding these mechanisms should provide avenues for novel therapeutic strategies to treat pathological processes such as tumor metastasis and chronic inflammatory disease.

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Section: Fig 2 (A)mentioning

confidence: 99%

Regulating cell migration: calpains make the cut

Franco

Huttenlocher

2005

Journal of Cell Science

437

406

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“…Calpain and calpastatin are predominantly cytosolic proteins, indicating that calpain must somehow escape the inhibitory control of calpastatin to become fully activated. It has been suggested that subcellular compartmentalization of either calpain or calpastatin may regulate calpain activity within cells (35,60). Modulation of the balance between protein levels of calpain relative to calpastatin could also represent a mechanism for regulating calpain activity.…”

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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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“…At a molecular level calpastatin protein undergoes structural modifications determining its specificity and inhibitory efficiency (13,45) as well as its intracellular localization. This is particularly evident in neuroblastoma cells (46), in which calpastatin is normally present in a phosphorylated and aggregated form localized in a specific position close to the nucleus. After hydrolysis of these phosphate groups by a protein phosphatase, the dephosphorylated inhibitor diffuses into the cytosol and acquires a significant increase in its inhibitory efficiency (45).…”

Section: Discussionmentioning

confidence: 99%

Age-dependent Degradation of Calpastatin in Kidney of Hypertensive Rats

Averna¹,

Tullio²,

Salamino³

et al. 2001

Journal of Biological Chemistry

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Hypertensive rats from the Milan strain show a significant decrease in calpastatin activity as compared with normotensive control animals. Calpastatin deficiency is age-related and highly relevant in kidney, heart, and erythrocytes and of minor entity in brain tissue. In normotensives the changes during aging in the levels of calpastatin activity and mRNA are consistent with an increase of calpastatin protein. In hypertensive rats such a relationship during aging is not observed, because a progressive accumulation of mRNA is accompanied by a lower amount of calpastatin protein as compared with control rats. Together with the low level of calpastatin in kidney of hypertensive rats, a progressive accumulation of an active 15-kDa calpastatin fragment, previously shown to represent a typical product of calpain-mediated calpastatin degradation, is also observed. Evidence for such intracellular proteolysis by Ca 2؉ -activated calpain is provided by the normalization of the calpastatin level, up to that of control animals, in hypertensive rats treated with drugs known to reduce both blood pressure and intracellular Ca 2؉ influx. Further evidence is provided by the disappearance, in these conditions, of the 15-kDa calpastatin fragment. These data allow the conclusion that calpastatin degradation is a relevant part of the overall mechanism for regulating calpain activity.

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Changes in intracellular localization of calpastatin during calpain activation

Cited by 61 publications

References 15 publications

Regulating cell migration: calpains make the cut

Regulating cell migration: calpains make the cut

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

Age-dependent Degradation of Calpastatin in Kidney of Hypertensive Rats

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