Disease relevance of Tln1

• Clostridium difficile toxin B induces reorganization of actin, vinculin, and talin in cultured cells [1].
• Along with F-actin, the adhesion plaque proteins, vinculin and talin were localized in intoxicated cells in a patchy pattern reminiscent of that seen in cells treated with phorbol esters or transformed by oncogenic viruses [1].

High impact information on Tln1

• Regulation of vinculin binding to talin and actin by phosphatidyl-inositol-4-5-bisphosphate [2].
• Phosphothreonine-mimicking mutations inhibit filamin, but not talin, binding, indicating that kinases may modulate this competition and provide additional means to control integrin functions [3].
• The molecular basis of filamin binding to integrins and competition with talin [3].
• Activation of PKC with phorbol esters results in the rapid disappearance of punctate staining of MARCKS, but not vinculin or talin, and is accompanied by cell spreading and loss of filopodia [4].
• We have studied the distribution of talin in J774 cells and mouse peritoneal macrophages undergoing Fc receptor-mediated phagocytosis [5].

Biological context of Tln1

• With the intention of using genetics in the study of talin, we identified a homologue to mouse talin in a genetic model system, the nematode Caenorhabditis elegans [6].
• Talin has two or more actin-binding sites, and three binding sites for the cytoskeletal protein vinculin [7].
• This article reviews the evidence (i) that the integrin beta-subunit cytoplasmic domain is important in the localization of integrins to focal adhesions, and for integrin-mediated cell adhesion/spreading; and (ii) that the integrin beta-subunit can be linked to F-actin via the actin-binding proteins talin, alpha-actinin and filamin [7].
• Amino acid substitutions within a 127-residue segment of talin capable of binding vinculin confirmed the importance of two of the motifs and suggest that residues critical for binding are within a 16-residue region [8].
• We have generated a single point mutation in talin that renders it resistant to proteolysis by calpain [9].

Anatomical context of Tln1

• Talin is an essential component of focal adhesions that couples beta-integrin cytodomains to F-actin and provides a scaffold for signaling proteins [10].
• The expression of talin RNA was only slightly elevated in 3T3 cells following serum stimulation, and it remained largely unchanged in regenerating liver [11].
• 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 [2].
• Disruption of the talin gene compromises focal adhesion assembly in undifferentiated but not differentiated embryonic stem cells [12].
• We conclude that changes in cell shape and motility of 5.51 compared to wild-type F9 cells are due to the absence of vinculin even though there may be functions of other focal adhesion complex proteins, e.g., talin, linking the actin cytoskeleton to the plasma membrane [13].

Associations of Tln1 with chemical compounds

• Talin binding disrupts the salt bridge between the alpha/beta tails, leading to tail separation and integrin activation [14].
• Indeed, binding of talin present in rat brain extracts to a glutathione S-transferase integrin beta1-cytodomain polypeptide was inhibited by the PIP kinase peptide [10].
• Recently, the integrin beta3 cytodomain and phosphatidylinositol phosphate (PIP) kinase type 1gamma (a phosphatidylinositol 4,5-bisphosphate-synthesizing enzyme) were shown to bind to the talin FERM domain (subdomain F3) [10].
• Two tyrosine residues flanking the SPLH motif (Tyr-644 and Tyr-649) have been implicated in the regulation of talin binding [15].
• Modeling studies suggest that phosphorylation of Tyr-649 will likewise have little effect on talin binding, whereas phosphorylation of the SPLH serine is predicted to be strongly disruptive [15].

Physical interactions of Tln1

• Phosphatidylinositol phosphate kinase type 1gamma and beta1-integrin cytoplasmic domain bind to the same region in the talin FERM domain [10].
• Isolation of peptides from phage-displayed random peptide libraries that interact with the talin-binding domain of vinculin [8].
• We show that talin physically interacts with CR3/alpha(M)beta(2) and that this interaction involves the talin head domain and residues W747 and F754 in the beta(2) integrin cytoplasmic domain [16].

Enzymatic interactions of Tln1

• 1,25-Dihydroxyvitamin D3 and macrophage colony-stimulating factor-1 synergistically phosphorylate talin [17].

Regulatory relationships of Tln1

• Talin immunostaining was widespread throughout control cells but was localized to the periphery 8 h after treatment with TPA or with inhibitors of PKC and calpain [18].
• This suggests that the local association of talin with these sites is induced by the cytoplasmic tail of beta 1 integrin receptor presented by the chimeric protein [19].
• These combined results suggest a model in which the reciprocal actions of Src tyrosine kinase and Shp-1 tyrosine phosphatase dynamically regulate the association between PIPKI gamma661 and talin [20].

Other interactions of Tln1

• Adhesive area strongly modulated adhesion strength, integrin binding, and vinculin and talin recruitment, exhibiting linear increases for small areas [21].
• Undifferentiated talin (-/-) ES cell mutants are unable to assemble focal adhesions when plated on fibronectin, whereas vinculin (-/-) ES cells are able to do so [7].
• We conclude that talin is essential for beta1 integrin expression and focal adhesion assembly in undifferentiated ES cells, but that a subset of differentiated cells are talin independent for both characteristics [12].
• In contrast, the transfection of vinculin constructs deficient in amino acids 1-288 (containing the talin- and alpha-actinin-binding site) or substituting tyrosine for phenylalanine (phosphorylation site, amino acid 822) in F9Vin(-/-) cells resulted in partial restoration of stiffness [22].
• In wild-type cells, Vav constitutively associated with the cytoskeletal membrane anchors talin and vinculin [23].

Analytical, diagnostic and therapeutic context of Tln1

• The expression of the adherens junction proteins vinculin, alpha-actinin, and talin was compared in serum-stimulated 3T3 cells and in regenerating rat liver following partial hepatectomy [11].
• Focal adhesion components (vinculin, talin, alpha-actinin) localized to adhesion plaques were isolated from bulk cytoskeletal and cytoplasmic components by mechanical rupture at a plane close to the basal cell surface and quantified by Western blotting [24].
• Immunofluorescence experiments show that both the ECMr antigens and the cytoskeletal proteins vinculin and talin are enriched on the cell processes and ventral surfaces of trophectoderm cells in embryo outgrowths, in patterns similar to those seen in fibroblasts, and consistent with their role in adhesion of the trophoblast cells to the substratum [25].
• However, talin did bind to GST-Vd1 in pull-down assays, and isothermal titration calorimetry measurements indicate a K(d) of approximately 9 mum [26].
• Three vinculin binding sites (VBS1-3) have previously been identified in the talin rod using a yeast two-hybrid assay [27].

References