Disease relevance of TLN1

• Deletions in 9p have been implicated in a variety of cancers, including malignant melanoma, and the concept that talin might be a candidate tumour suppressor gene is discussed [1].
• Large amounts of talin also accumulated above and around invading Salmonella, but there was only a minor accumulation of vinculin around a few organisms [2].
• The interaction of IpaA(560-633) with VD1 is highly similar to the interaction of the endogenous, eukaryotic proteins talin and alpha-actinin with VD1, showing that Shigella uses a structural mimicry strategy to activate vinculin [3].
• In order to begin to investigate where the talin-binding domain is in vinculin, vinculin was digested with Staphylococcus aureus V8 protease to generate two major fragments of 85 and 30 kDa, and these fragments were purified [4].
• Perineurium talin immunoreactivity decreases in diabetic neuropathy [5].

High impact information on TLN1

• Structural basis of integrin activation by talin [6].
• We used structure-based mutagenesis to engineer talin and beta3 variants that interact with comparable affinity to the wild-type proteins but inhibit integrin activation by competing with endogenous talin [6].
• The interface interactions are disrupted by point mutations or the cytoskeletal protein talin that are known to activate the receptor [7].
• Here we show that the type I phosphatidylinositol phosphate kinase isoform-gamma 661 (PIPKI gamma 661), an enzyme that makes PtdIns(4,5)P(2), is targeted to focal adhesions by an association with talin [8].
• Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P(2)) regulates interactions between these proteins, including the interaction of vinculin with actin and talin [8].

Biological context of TLN1

• Our results also show that FAK can be localized independent of its phosphorylation and that cells can spread and induce localization of other focal adhesion proteins in the absence of detectable talin [9].
• Curiously, talin contains three noncontiguous vinculin binding sites (VBS) that can bind individually to the vinculin head (Vh) domain [10].
• Here, we demonstrate for the first time the in vivo relevance of this interaction by fluorescence resonance energy transfer between beta(3)-GFP and DsRed-talin fragment G [11].
• These results demonstrate that activation of the integrin-binding activity of talin requires not only integrin engagement to the extracellular matrix but also the binding of PI4,5P(2) to talin, suggesting a possible role of lipid metabolism in organizing the sequential assembly of focal adhesion components [12].
• In this report, we show that in talin-deficient AT22 cells, the aberrant glycosylation of integrin receptors is accompanied by a delay in the export of the integrin alpha5beta1 [13].

Anatomical context of TLN1

• A talin-dependent LFA-1 focal zone is formed by rapidly migrating T lymphocytes [14].
• Vinculin, talin, and integrins are localized at specific adhesion sites of malignant B lymphocytes [15].
• Talin links integrin beta cytoplasmic domains to the actin cytoskeleton and is involved in the clustering and activation of these receptors [16].
• Two-color fluorescence analysis of the transfected cells, spread on fibrinogen, revealed distinct subcellular staining patterns including focal adhesion, actin filament, and granular labeling for different talin fragments [11].
• The intracellular distribution of FAC proteins (paxillin, talin, and vinculin) was assessed by immunohistochemistry before, during, and after exposure of renal epithelial cells to metabolic inhibitors [17].

Associations of TLN1 with chemical compounds

• PIPKI gamma 661 is tyrosine phosphorylated by focal adhesion associated kinase signalling, increasing both the activity of phosphatidylinositol phosphate kinase and its association with talin [8].
• Tyrosine kinase inhibition also failed to block the ability of ligand occupancy plus integrin aggregation to trigger transmembrane accumulation of the three cytoskeletal molecules talin, alpha-actinin, and vinculin; these molecules accumulated even in the presence of cytochalasin D [18].
• When phosphoinositides were associated with phospholipid bilayer, talin/phosphoinositide association was restricted to PI4,5P(2) [12].
• Consistent with the view that talin must be activated at these sites, we found that phosphatidylinositol 4-monophosphate and phosphatidylinositol 4,5-bisphosphate (PI4,5P(2)) bound to talin in cells in suspension or at early stages of adhesion, respectively [12].
• This introduces a novel connection between talin and PIP2 generation [19].

Physical interactions of TLN1

• Vinculin is autoinhibited by an intramolecular interaction that masks binding sites for talin and F-actin [20].
• Calpain cleavage promotes talin binding to the beta 3 integrin cytoplasmic domain [16].
• The critical residues in the talin FERM domain that mediate integrin binding show a high degree of conservation in kindlerin [21].
• Furthermore, we have correlated the ability of integrin to induce FAK phosphorylation with its ability to bind talin using a mutant integrin lacking the carboxyl-terminal 13 amino acids [22].
• Here, we utilized "homology scanning" mutagenesis to identify beta tail mutants selectively defective in c-Src binding and found that amino acid exchanges affecting a combination of an Arg and Thr residue in the integrin beta3 tail control the binding specificity for SFKs but have no effect on talin binding [23].

Co-localisations of TLN1

• Integrin alpha-chains colocalized with talin, dependent on the matrix substrate [24].
• These two proteins share a region of homology with talin and members of the FERM superfamily of proteins.We have determined that a functional UNC-112::GFP fusion protein colocalizes with PAT-3/beta-integrin in both adult and embryonic body wall muscle [25].
• Hence, F-actin and the cytoskeletal protein talin co-localized with beta 1 and alpha 4 integrin clusters at sites of cell-cell contact [26].

Regulatory relationships of TLN1

• Here we report the crystal structure of the human Vh.VBS1 complex, a validated model of the Vh.VBS2 structure, and biochemical studies that demonstrate that all of talin VBSs activate vinculin by provoking helical bundle conversion of the Vh domain, which displaces the vinculin tail (Vt) domain [10].
• Moreover, the interaction between integrin and talin was greatly enhanced by PI4,5P(2)-induced talin activation [12].
• Talin controls the exit of the integrin alpha 5 beta 1 from an early compartment of the secretory pathway [13].
• PDGF stimulation induces phosphorylation of talin and cytoskeletal reorganization in skeletal muscle [27].
• ICAP-1 alpha induced a rapid disruption of focal adhesions, which may result from the ability of ICAP-1 alpha to inhibit the association of beta(1A) integrin with talin, which is crucial for the assembly of these structures [28].
• In this study using transfectants and T cells, we showed that talin induced an intermediate affinity alphaLbeta2 that adhered constitutively to its ligand intercellular adhesion molecule (ICAM)-1 but not ICAM-3 [29].

Other interactions of TLN1

• Yeast two-hybrid and biochemical analyses yielded interactions with several focal adhesion and/or cytoskeletal proteins including mena, zyxin and talin [30].
• An additional duplication subsequently produced a second Talin-2 in teleost fishes and a second Talin-1 in Xenopus laevis [31].
• We examined the progressive appearance of the following proteins: alpha, beta, gamma, delta-sarcoglycans, beta-dystroglycan, dystrophin, talin, vinculin and integrin isoform alpha(7)/beta(1) [32].
• These data show that the talin FERM domain, like that in the ERM proteins, is masked in the intact molecule [16].
• We propose that talin binding to the integrin may disclose a diphenylalanine export signal, which is present in the membrane-proximal GFFKR motif conserved in all integrin alpha chains [13].

Analytical, diagnostic and therapeutic context of TLN1

• To understand how talin recognizes integrin beta cytoplasmic domains, we configured surface plasmon resonance methodology to measure the interaction of talin with the beta3 integrin cytoplasmic domain [16].
• Both wild type and mutant alpha(IIb)beta(3), purified by RGD affinity chromatography, bound to a similar extent to immobilized talin [33].
• Finally, microinjection of anti-talin antibodies resulted in accumulation of the integrins within the cells [13].
• Northern blot analysis detected TLN expression in various human tissues, including leukocytes, lung, placenta, liver, kidney, spleen, thymus, colon, skeletal muscle, and heart [34].
• We have localized TLN to human chromosome band 9p13 by both fluorescence in situ hybridization and radiation hybrid mapping [34].

References