Calpain Cleavage of the Cytoplasmic Domain of the Integrin β2 Subunit

Du, Xiaoping; Saido, Takaomi C.; Tsubuki, Satoshi; Indig, Fred E.; Williams, Michael J.; Ginsberg, Mark H.

doi:10.1074/jbc.270.44.26146

Cited by 170 publications

(170 citation statements)

References 44 publications

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“…In fact, the cytosolic domain of integrin requires membrane localization to promote apoptosis, 58 and it is possible that calpain-mediated cleavage of the b-integrin cytosolic domain observed in ECM-deprived cells may even act to delay apoptosis by preventing IMD. 72 Despite these differences, the parallels between the APP and integrin systems are compelling, and the functional colocalization of the receptors leaves open the possibility that these elements may act coordinately to regulate the same 'dependence pathway.' A comparison of integrins and canonical dependence receptors is shown in Table 2.…”

Section: Proteolytic Cleavage Of the Integrin Cytosolic Domainmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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In the absence of their cognate ligand, dependence receptors trigger programmed cell death. This function is the defining feature of dependence receptors, which include members of several different protein families. The integrins are a family of heterodimeric receptors for extracellular matrix (ECM) proteins, mediating cell anchorage and migration. Integrins share characteristics with dependence receptors, and integrin binding to substrate ECM ligands is essential for cell survival. Although integrins do not conform in all characteristics to the established definitions of dependence receptors, alterations in the expression of integrins and their ligands during physiological and pathological events, such as wound healing, angiogenesis and tumorigenesis, do regulate cell fate in a ligand-dependent manner. This biosensory function of integrins fits well with our current concept of dependence receptor action, and thus integrins may rightly be considered to comprise a distinct subclass of dependence receptor.

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Section: Proteolytic Cleavage Of the Integrin Cytosolic Domainmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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“…Calpain induces cleavage of many signaling molecules and cytoskeletal proteins (7, 19 -23). In addition, calpain cleaves the cytoplasmic domain of the ␤ 1 -and ␤ 3 -integrins (24,25). We showed that one of the consequences of calpain activation in cultured cells was the formation of clusters of integrin that appear to contain Rac-binding protein(s) and to be required for the activation of Rac (17).…”

mentioning

confidence: 93%

“…1 (see below), calpain cleaves the cytoplasmic domain of ␤ 3 -integrin at five sites between amino acid residues 735 and 760 (24). Thus, calpain-cleaved integrin in the early integrin clusters would be unable to interact with any molecules requiring this region of the cytoplasmic domain.…”

mentioning

confidence: 99%

Dynamic Modulation of Cytoskeletal Proteins Linking Integrins to Signaling Complexes in Spreading Cells

Reddy

Białkowska

Fox

2001

Journal of Biological Chemistry

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Recently we showed that signaling across ␤ 3 -integrin leads to activation of calpain and formation of integrin clusters that are involved in Rac activation. The subsequent activation of Rac and Rho leads to the formation of focal complexes and focal adhesions, respectively. The goal of the present study was to determine whether different proteins link the integrin to the cytoskeleton in the different complexes. We show that talin is present in focal adhesions but not in the calpain-induced clusters. ␣-Actinin colocalized with integrin at various sites, including the calpain-induced clusters. Skelemin, a protein shown recently to interact with ␤ 1 -and ␤ 3 -integrin in vitro, colocalized with integrin in calpain-induced clusters but was absent from focal adhesions. Cells transiently expressing skelemin C2 motifs, which contain the integrin binding site, failed to form integrin clusters or to spread on a substrate for ␤ 1 -and ␤ 3 -integrins. These results 1) suggest a dynamic reorganization of integrin complexes during cell spreading, 2) show that different cytoskeletal proteins link integrins in different complexes, and 3) demonstrate that skelemin is responsible for linking integrin to the calpain-induced clusters, and 4) show that the integrin-skelemin interaction is essential for transmission of signals leading to the initial steps of cell spreading.

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“…The hydrophobicity of the N-terminal domain (domain V) has been taken as an indication of its role in membrane anchoring (Kuboki et al, 1987(Kuboki et al, , 1990Inomata et al, 1989Inomata et al, , 1990Lee et al, 1990;Molinari et al, 1994;Moldoveanu et al, 2002Moldoveanu et al, , 2003Khorchid and Ikura, 2002;Pal et al, 2003). Calpains have potential biological functions in apoptosis, the pathology of degenerative diseases, and mediating intracellular calcium signals (Nicotera et al, 1986;Du et al, 1995;Spencer et al, 1995;Arora et al, 1996;Huang and Wang, 2001;Glading et al, 2002). A number of studies indicated that calpains have a role in the cell cycle, specifically in the G 1 to S transition (reviewed in Goll et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Identification of calpain cleavage sites in the G1 cyclin-dependent kinase inhibitor p19INK4d

Joy

Nalabothula

Ghosh

et al. 2006

Biological Chemistry

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Calpains are a large family of Ca 2q -dependent cysteine proteases that are ubiquitously distributed across most cell types and vertebrate species. Calpains play a role in cell differentiation, apoptosis, cytoskeletal remodeling, signal transduction and the cell cycle. The cell cycle proteins cyclin D1 and p21 KIP1 , for example, have been shown to be affected by calpains. However, the rules that govern calpain cleavage specificity are poorly understood. We report here studies on the pattern of m-calpain proteolysis of the p19 INK4d protein, a cyclin-dependent kinase 4/6 inhibitor that negatively regulates the mammalian cell cycle. Our data show new characteristics of calpain action: m-calpain cleaves p19 INK4d immediately after the first and second ankyrin repeats that are structurally less stable compared to the other repeats. This is in contrast to features observed so far in the specificity of calpains for their substrates. These results imply that calpain may be involved in the cell cycle by regulating the cell cycle regulatory protein turnover through CDK inhibitors and cyclins.

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Calpain Cleavage of the Cytoplasmic Domain of the Integrin β2 Subunit

Abstract: The cytoplasmic domains of integrin ␤ subunits are involved in bidirectional transmembrane signaling. We report that the cytoplasmic domain of the integrin ␤

Cited by 170 publications

References 44 publications

Integrins as a distinct subtype of dependence receptors

Integrins as a distinct subtype of dependence receptors

Dynamic Modulation of Cytoskeletal Proteins Linking Integrins to Signaling Complexes in Spreading Cells

Identification of calpain cleavage sites in the G1 cyclin-dependent kinase inhibitor p19INK4d

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