Regulation of vinculin binding to talin and actin by phosphatidyl-inositol-4-5-bisphosphate

Abstract

Vinculin, a prominent cytoskeletal protein at cell-substrate adhesions (focal adhesions) and cell-cell adhesions (adherens junctions), interacts with other cytoskeletal proteins, including talin and actin. An intramolecular interaction between the head and tail domains of vinculin masks the binding sites for both proteins. The exposure of cryptic binding sites may be important for promoting focal adhesion assembly. Several agents that induce the formation of focal adhesions act through the GTP-binding protein Rho, which elevates phosphatidylinositol-4,5-bisphosphate (PtdInsP2) levels by activating phosphatidyl-inositol-4-phosphate-5-OH kinase (PtdIns-5-OH kinase). PtdInsP2 regulates several actin-binding proteins, including profilin, gelsolin and alpha-actinin, and interacts with vinculin. Here we report that PtdInsP2 dissociates vinculin's head-tail interaction, unmasking its talin- and actin-binding sites. Microinjection of antibodies against PtdInsP2 inhibit assembly of stress fibres and focal adhesions.

Phosphatidylinositol 4,5‐bisphosphate specifically stimulates PP60c‐src catalyzed phosphorylation of gelsolin and related actin‐binding proteins

“…Based on the structural and functional similarties between members of the gelsolin family, we hypothesize that severin from Dictyostelium discoideum and villin are also candidates for pp60 c~src phosphorylation. A similar role for PIP 2 may also apply to other cytoskeleton regulatory proteins involved in signal transduction pathways leading to microfilament rearrangements, such as vinculin [60] and cc-actinin [61].…”

Signaling by integrin receptors

“…The increase in PIP 2 synthesis by Rho A is potentially relevant to focal adhesion assembly because the actin binding activity of several cytoskeletal proteins such as pro®lin and gelsolin is modulated by PIP 2 in vitro (Hartwig et al, 1995) and PIP 2 is enriched in focal adhesion plaques. In light of this, Gilmore and Burridge (1996) reported that the association of PIP 2 with vinculin induces a conformational change in vinculin, allowing it to interact with talin, which binds actin. Furthermore they showed that injection of anti-PIP 2 antibodies into ®broblasts inhibited LPA/Rhoinduced stress ®bers and focal adhesion formation, suggesting a role for PIP 2 in focal adhesion and stress ®ber assembly.…”

Reversal of Aging‐Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein‐Protein Interfaces

“…Based on the widely known importance of interactions of vinculin with talin in the FA,44, 45 we designed a peptide (TLN‐VCL) mimicking a vinculin binding site on talin. There are several talin‐vinculin binding sites, and although several of these sequences had no effect on smooth muscle cell function, the sequence GRPLLQAAKGLAGAVSELLRSAQPA was effective.…”