Organization of the human gene encoding the cytoskeletal protein vinculin and the sequence of the vinculin promoter.

Moiseyeva, Elena P.; Weller, P A; Zhidkova, Natalia I.; Corben, E B; Patel, Bipin; Jasinska, I; Koteliansky, Victor; Critchley, David R.

doi:10.1016/s0021-9258(18)53612-7

Cited by 49 publications

(6 citation statements)

References 58 publications

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“…On the other hand, in cardiac myocytes, an organized actin cytoskeleton was found to be essential for RhoA-dependent activation of SRF (Wei et al, 2001). SRF itself controls the expression of genes encoding cytoskeletal proteins, including vinculin and different actins (Frederickson et al, 1989;Sartorelli et al, 1990;Lee et al, 1991;Moiseyeva et al, 1993;Mack and Owens, 1999).…”

Section: Introductionmentioning

confidence: 99%

Serum response factor is crucial for actin cytoskeletal organization and focal adhesion assembly in embryonic stem cells

Schratt

Philippar

Berger

et al. 2002

The Journal of Cell Biology

176

163

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The activity of serum response factor (SRF), an essential transcription factor in mouse gastrulation, is regulated by changes in actin dynamics. Using Srf(−/−) embryonic stem (ES) cells, we demonstrate that SRF deficiency causes impairments in ES cell spreading, adhesion, and migration. These defects correlate with defective formation of cytoskeletal structures, namely actin stress fibers and focal adhesion (FA) plaques. The FA proteins FA kinase (FAK), β1-integrin, talin, zyxin, and vinculin were downregulated and/or mislocalized in ES cells lacking SRF, leading to inefficient activation of the FA signaling kinase FAK. Reduced overall actin expression levels in Srf(−/−) ES cells were accompanied by an offset treadmilling equilibrium, resulting in lowered F-actin levels. Expression of active RhoA-V14 rescued F-actin synthesis but not stress fiber formation. Introduction of constitutively active SRF-VP16 into Srf(−/−) ES cells, on the other hand, strongly induced expression of FA components and F-actin synthesis, leading to a dramatic reorganization of actin filaments into stress fibers and lamellipodia. Thus, using ES cell genetics, we demonstrate for the first time the importance of SRF for the formation of actin-directed cytoskeletal structures that determine cell spreading, adhesion, and migration. Our findings suggest an involvement of SRF in cell migratory processes in multicellular organisms.

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Section: Introductionmentioning

confidence: 99%

Serum response factor is crucial for actin cytoskeletal organization and focal adhesion assembly in embryonic stem cells

Schratt

Philippar

Berger

et al. 2002

The Journal of Cell Biology

176

163

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“…Vinculin links the integrin adhesion complex to the filamentous actin network and evidences suggest that metavinculin play a similar role along with vinculin with enhanced force transduction, however, its muscle-specific remains to be identified. 29,37,39,52,55,57,84 Here, downregulated DEGs in metavinculin-depleted cells are associated with focal adhesion, adherens, anchoring and cell-substrate junctions in skeletal muscle cells as metavinculin is necessary to stabilize these complexes similar to vinculin (Figure S6A). The major functional difference reported between vinculin and metavinculin lays in the actin bundling.…”

Section: Discussionmentioning

confidence: 98%

“…The major functional difference reported between vinculin and metavinculin lays in the actin bundling. 42,58,[61][62][63] Metavinculin may fine-tune actin organisation in skeletal muscles as downregulated DEGs in metavinculin-depleted cells associates with actin bundling terms (Figure S4A). 58,59,61,63 Moreover, we have identified the unique role metavinculin in skeletal muscle differentiation through depletion and ectopic expression studies.…”

Section: Metavinculin Critically Regulates Muscle Cell Proliferation ...mentioning

confidence: 99%

“…31 Metavinculin, a longer muscle-specific splice variant of vinculin generated by alternative splicing of exon 19 that encodes 68-amino acid residues, is co-localized with vinculin at the costameres, sarcolemma, I band in the sarcomere and intercalated discs. [32][33][34][35][36][37] Its expression was reported in smooth, cardiac, skeletal muscles and platelets. [38][39][40][41][42] Metavinculin loss or point mutations at its unique exon is linked with dilated and hypertrophic cardiomyopathies.…”

Section: Introductionmentioning

confidence: 99%

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Metavinculin mediates differentiation cues into myogenic gene expression

Murugan,

Nanjegowda,

Jothi

2024

Preprint

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Skeletal muscle differentiation is a highly orchestrated process where muscle progenitors fuse to give mature contractile muscle. Ubiquitous to muscle-specific isoform switching helps muscle cells to adapt to various physiological needs. However, how they decipher differentiation signals into myogenic transcription remains unexplored. Metavinculin, a muscle-specific isoform of ubiquitous cytoskeletal scaffold protein vinculin, is involved in actin remodeling and force transduction along with vinculin in muscle cells. Although it is exclusively expressed in muscle cells, its muscle-specific role has yet to be identified. Here, we report the novel function of metavinculin in switching canonical to non-canonical Wnt-signaling to execute skeletal muscle differentiation. Specifically, we have found that metavinculin expression is absent in proliferating myoblasts and is expressed during skeletal muscle differentiation and in vivo regeneration. Splicing factor Rbfox1 is responsible for the metavinculin-specific exon retention by direct binding to its downstream intron during muscle differentiation. Further, metavinculin depletion dampens the skeletal muscle differentiation program while its ectopic expression induces differentiation-associated genes even in growth-promoting conditions. Additionally, metavinculin-depletion downregulates muscle development and upregulates stress-responsive genes with deregulated Wnt-pathway. Subsequent experiments showed that pharmacological canonical Wnt-activation impedes muscle differentiation program, whereas its inhibition stimulates differentiation in growth conditions. Canonical Wnt-inhibition or non-canonical Wnt7b ectopic expression can restore muscle differentiation programs in metavinculin-depleted cells. Overall, these evidences reveal the dynamic interplay of Rbfox1-generated metavinculin in switching canonical to non-canonical Wnt-signaling through Wnt7b to establish skeletal muscle differentiation.

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“…To define this site further, we used the yeast two-hybrid system to analyse the effect of both N-terminal and C-terminal deletions on binding to each of the three vinculin-binding sites in talin. Deletions were made in accordance with exon boundaries [43]. C-terminal deletions to vinculin residues 208 and 167 failed to compromise binding to any of the three vinculin-binding sites in talin (Figure 5A), indicating that vinculin residues 1-167 contain a complete talin-binding site.…”

Section: Further Definition Of the Talin-binding Site In Vinculinmentioning

confidence: 99%

Talin contains three similar vinculin-binding sites predicted to form an amphipathic helix

Bass

Smith

Prigent

et al. 1999

Biochemical Journal

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Using recombinant talin polypeptides and an SDS/PAGE-blot overlay assay, we have previously identified three regions of talin that are involved in binding to vinculin [Gilmore, Wood, Ohanian, Jackson, Patel, Rees, Hynes and Critchley (1993) J. Cell Biol. 122, 337-347]. We have confirmed these observations by using a yeast two-hybrid assay and shown that talin residues 498-656, 852-950 and 1929-2029 are each capable of binding to vinculin residues 1-258. We have further defined the three vinculin-binding sites in talin to residues 607-636, 852-876 and 1944-1969; alignment of these sequences shows 59% similarity, although there are only two identical residues. Predictions of secondary structure indicate that this vinculin-binding motif forms an amphipathic alpha-helix. The hydrophobic face of helix 607-636 contains three aligned leucines (residues 608, 615 and 622), which show conservative substitutions in the other two sites. To test the possibility that this might constitute a leucine zipper involved in vinculin binding, we mutated each leucine residue to an alanine. The results showed that this leucine repeat is not essential to the interaction between talin and vinculin. We also used the yeast two-hybrid system to define further the talin-binding site within vinculin residues 1-258. C-terminal deletions made in accordance with exon boundaries showed that vinculin residues 1-167 are capable of interacting with each of the three vinculin-binding sites in talin. However, all N-terminal deletions abolished binding. The results suggest that the talin-binding site in vinculin has a relatively complex fold, whereas the vinculin-binding motif in talin is contained within a short linear peptide sequence that is repeated three times in the talin rod domain.

show abstract

Organization of the human gene encoding the cytoskeletal protein vinculin and the sequence of the vinculin promoter.

Cited by 49 publications

References 58 publications

Serum response factor is crucial for actin cytoskeletal organization and focal adhesion assembly in embryonic stem cells

Serum response factor is crucial for actin cytoskeletal organization and focal adhesion assembly in embryonic stem cells

Metavinculin mediates differentiation cues into myogenic gene expression

Talin contains three similar vinculin-binding sites predicted to form an amphipathic helix

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