Not just scaffolding: plectin regulates actin dynamics in cultured cells

Andrä, Kerstin; Nikolic, Branislav; Stöcher, Markus; Drenckhahn, Detlev; Wiche, Gerhard

doi:10.1101/gad.12.21.3442

Cited by 194 publications

(192 citation statements)

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“…(11,(16)(17)(18)(19) It is known that ablation of plectin by siRNA in MCF7 epithelial cells had a negative effect on their migratory capacity, (20) and that the distribution of vimentin structures is altered in mitotic plectin-deficient fibroblasts. (21) Plectin has been shown to be a direct target of mitotic cyclindependent kinase 1 ⁄ cyclin B (CDK1 ⁄ CycB) kinase.…”

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confidence: 99%

“…(13)(14)(15) Moreover, it is known that plectin belongs to the plakin family and that has been shown to interact with microtubules, actin filaments, and intermediate filaments (IFs) such as vimentin, cytokeratin, and desmin, and plays a very important role in maintaining cell structure and mediating the mechanical integration of cells and tissues. (11,(16)(17)(18)(19) It is known that ablation of plectin by siRNA in MCF7 epithelial cells had a negative effect on their migratory capacity, (20) and that the distribution of vimentin structures is altered in mitotic plectin-deficient fibroblasts. (21) Plectin has been shown to be a direct target of mitotic cyclindependent kinase 1 ⁄ cyclin B (CDK1 ⁄ CycB) kinase.…”

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confidence: 99%

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BRCA2 interacts with the cytoskeletal linker protein plectin to form a complex controlling centrosome localization

et al. 2009

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The breast cancer susceptibility gene (BRCA2) is localized mainly in the nucleus where it plays an important role in DNA damage repair. Some BRCA2 protein is also present in the centrosome. Here, we demonstrate that BRCA2 interacts with plectin, a cytoskeletal cross-linker protein, and that this interaction controls the position of the centrosome. Phosphorylation of plectin by cyclindependent kinase 1 ⁄ cyclin B (CDK1 ⁄ CycB) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of HeLa cells by adding activated CDK1 ⁄ CycB kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. Plectin has six homologous ankyrin-like repeat domains (termed PLEC M1-M6). Using a pull-down assay, we found that GST-PLEC M1 and a GST-C-terminal region fusion protein (which comprised PLEC M6, along with an adjacent vimentin site) interacted with BRCA2. Since each PLEC module exhibits high homology to the others, the possibility of all six domains participating in this interaction was indicated. Moreover, when PLEC M1 was overexpressed in HeLa cells, it competed with endogenous plectin and inhibited the BRCA2-plectin interaction. This inhibitory effect resulted in dissociation of the centrosomes from the nucleus and increased the rate of micronuclei formation which may lead to carcinogenesis. In addition, when either BRCA2 or plectin was suppressed by the appropriate siRNA, a similar change in centrosomal positioning was observed. We suggest that the BRCA2-plectin interaction plays an important role in the regulation of centrosome localization and also that displacement of the centrosome may result in genomic instability and cancer development. (Cancer Sci 2009; 100: 2115-2125 M utations of breast cancer susceptibility gene (BRCA2), a tumor suppressor gene, are associated with an increased susceptibility to breast and ovarian carcinomas.(1,2) The BRCA2 protein plays important roles in both transcriptional regulation and DNA damage repair mediated by homologous recombination.(3,4) BRCA2 forms complexes with Rad51 that are important for the maintenance of genomic stability during DNA recombination and double-strand break repair.(5,6) Murine embryo fibroblasts that are homozygous for a targeted mutation of Brca2 (BRCA2Tr2014) show centrosome amplification, spontaneous accumulation of chromosomal abnormalities, and defective cytokinesis. (7,8) Recently, we reported that BRCA2 interacts with c-tubulin (a component of the centrosome), has nuclear export and centrosome localization signals, and localizes to the centrosomes during the S and early M phases of the cell cycle.(9,10) Moreover, suppression of BRCA2 using small interfering RNA (siRNA) causes abnormalities in the position or duplication of the centrosome.(7,10) Nevertheless, despite these observations, the function of BRCA2 with respect to the centrosome remains uncertain.Here, we demonstrate that plectin, a cytoskeletal cross-linker protein widel...

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BRCA2 interacts with the cytoskeletal linker protein plectin to form a complex controlling centrosome localization

et al. 2009

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“…However, to date no experimental evidence for this assumption has been published to our knowledge. The N-terminal globular domain of plectin harbors an actin binding domain 12 and regions for integrin ␤4 binding. 9,10 The importance of this region has also been demonstrated by a three amino-acid deletion in the Nterminal globular domain of plectin in a patient with EBS with muscular dystrophy.…”

Section: Discussionmentioning

confidence: 99%

“…5 Plectin is involved in the formation of hemidesmosomes of epithelial cells 6 and links Z-disks to the intermediate filament network in skeletal muscle fibers. 7 Using deletion studies and overlay assays the binding domains for vimentin/ keratin filaments, 8 integrin ␤4, 9,10 desmin, 11 and actin 12,13 have been identified. No particular sequence has been identified for homodimer formation.…”

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A Compound Heterozygous One Amino-Acid Insertion/Nonsense Mutation in the Plectin Gene Causes Epidermolysis Bullosa Simplex with Plectin Deficiency

Bauer¹,

Rouan

Kofler³

et al. 2001

The American Journal of Pathology

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Plectin is a cytoskeleton linker protein expressed in a variety of tissues including skin, muscle, and nerves. Mutations in its gene are associated with epidermolysis bullosa simplex with late-onset muscular dystrophy. Whereas in most of these patients the pathogenic events are mediated by nonsense-mediated mRNA decay, the consequences of an in-frame mutation are less clear. We analyzed a patient with compound heterozygosity for a 3-bp insertion at position 1287 leading to the insertion of leucine as well as the missense mutation Q1518X leading to a stop codon. The presence of plectin mRNA was demonstrated by a RNase protection assay. However, a marked reduction of plectin protein was found using immunofluorescence microscopy of the patient's skin and Western blot analysis of the patient's cultured keratinocytes. The loss of plectin protein was associated with morphological alterations in plectin-containing structures of the dermo-epidermal junction, in skeletal muscle, and in nerves as detected by electron microscopy. In an in vitro overlay assay using recombinant plectin peptides spanning exons 2 to 15 the insertion of leucine resulted in markedly increased self-aggregation of plectin peptides. These results describe for the first time the functional consequences of an in-frame insertion mutation in humans.

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“…Plectin plays important roles in a number of cell functions including migration and wound healing [22]. Plectin has been shown to activate RhoA GTPase [23].…”

Section: Possible Biological and Pathological Meaning Of The Binding mentioning

confidence: 99%

Analysis of β-Amyloid Peptide -Binding Proteins in Microglial Cells

Ito¹

2012

TOGERIMJ

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Alzheimer's disease is the most common form of dementia in the elderly. Although -amyloid peptide (A ) has been considered major cause of Alzheimer pathology, molecular and cellular mechanisms of the disease development of Alzheimer have not been clarified yet. Presently A has been considered to induce neural cell death by direct penetration of aggregated form or indirect cell death by inflammatory responses induced by A -activated microglia. In order to understand A induced microglial activation, we searched the proteins which bind to A in activated microglial cell line. We stimulated Ra2 microglial cell line with A . Activated Ra2 cells were immunoprecipitated with anti-A and run the gel. Membrane was silver stained and bands were cut and digested with enzyme. They were analyzed by LC/MS/MS. We found that several proteins including myosin 9 and actin bound to A . By the addition of A , actin binding was enhanced and other proteins including IQGAP1, Plectin strongly bound to A . These results indicate that A binds to the proteins belonging to cellular cytoskeletal system.

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Not just scaffolding: plectin regulates actin dynamics in cultured cells

Cited by 194 publications

References 44 publications

BRCA2 interacts with the cytoskeletal linker protein plectin to form a complex controlling centrosome localization

BRCA2 interacts with the cytoskeletal linker protein plectin to form a complex controlling centrosome localization

A Compound Heterozygous One Amino-Acid Insertion/Nonsense Mutation in the Plectin Gene Causes Epidermolysis Bullosa Simplex with Plectin Deficiency

Analysis of β-Amyloid Peptide -Binding Proteins in Microglial Cells

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