Alternative titles; symbols
HGNC Approved Gene Symbol: TLN1
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38): 9:35,696,948-35,732,195 (from NCBI)
Talin links vinculin (193065) to the integrins, and, thus, the cytoskeleton to extracellular matrix (ECM) receptors. It has a mass of 270 kD and shares 23% N-terminal identity with ezrin (123900), which has similar functions (Rees et al., 1990).
Di Paolo et al. (2002) and Ling et al. (2002) presented evidence that talin, through its FERM domain, interacts with the C-terminal tail of the 90-kD PIP5K1C (606102) isoform. The authors showed that this interaction induces clustering of PIP5K1C and talin at focal adhesions and increases the local production of phosphatidylinositol-4,5-bisphosphate.
Mechanical forces on matrix-integrin-cytoskeleton linkages are crucial for cell viability, morphology, and organ function. The production of force depends on the molecular connections from ECM-integrin complexes to the cytoskeleton. The minimal matrix complex causing integrin-cytoskeleton connections is a trimer of fibronectin's (135600) integrin-binding domain FNIII7-10. Jiang et al. (2003) reported a specific molecular slip bond that was repeatedly broken by a force of 2 pN at the cellular loading rate of 60 nm/second; this occurred with single trimer beads but not with the monomer. Talin-1, which binds to integrins and actin filaments in vitro, is required for the 2-pN slip bond and rapid cytoskeleton binding. Furthermore, Jiang et al. (2003) showed that inhibition of fibronectin binding to alpha-v-beta-3 integrin (193210 and 173470) and deletion of beta-3 markedly decreased the 2-pN force peak. They suggested that talin-1 initially forms a molecular slip bond between closely packed fibronectin-integrin complexes and the actin cytoskeleton, which can apply a low level of force to fibronectin until many bonds form or a signal is received to activate a force response.
Tadokoro et al. (2003) reported that specific binding of the cytoskeletal protein talin to integrin beta subunit (135630) cytoplasmic tails leads to the conformational rearrangements of integrin extracellular domains that increase their affinity. They found that regulated binding of talin to integrin beta tails is a final common element of cellular signaling cascades that control integrin activation.
Hu et al. (2007) developed correlational fluorescent speckle microscopy to measure the coupling of focal adhesion proteins to actin filaments (see 102610). Different classes of focal adhesion structural and regulatory molecules exhibited varying degrees of correlated motions with actin filaments, indicating hierarchical transmission of actin motion through focal adhesions. Interactions between vinculin (193065), talin, and actin filaments appear to constitute a slippage interface between the cytoskeleton and integrins, generating a molecular clutch that is regulated during the morphodynamic transitions of cell migration.
Kanchanawong et al. (2010) used 3-dimensional super-resolution fluorescence microscopy to map nanoscale protein organization in focal adhesions. Their results revealed that integrins and actin are vertically separated by an approximately 40-nm focal adhesion core region consisting of multiple protein-specific strata: a membrane-apposed integrin signaling layer containing integrin cytoplasmic tails (see 193210), focal adhesion kinase (600758), and paxillin (602505); an intermediate force-transduction layer containing talin and vinculin; and an uppermost actin-regulatory layer containing zyxin (602002), vasodilator-stimulated phosphoprotein (601703), and alpha-actinin (102575). By localizing amino- and carboxy-terminally tagged talins, Kanchanawong et al. (2010) revealed talin's polarized orientation, indicative of a role in organizing the focal adhesion strata. Kanchanawong et al. (2010) concluded that their composite multilaminar protein architecture provided a molecular blueprint for understanding focal adhesion functions.
Shen et al. (2013) demonstrated that G-alpha-13 (604406) and talin bind to mutually exclusive but distinct sites within the integrin beta-3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signaling and also ligand-induced integrin activation, but is not required for outside-in signaling. Integrin ligation induces transient talin dissociation and G-alpha-13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signaling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of G-alpha-13-integrin interaction selectively abolishes outside-in signaling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Shen et al. (2013) concluded that they discovered a mechanism for the directional switch of integrin signaling and, on the basis of this mechanism, designed a potent antithrombotic drug that does not cause bleeding.
By analyzing tissue samples from Talin1-deficient mice, Lim et al. (2020) showed that Talin1 regulated integrin-dependent migration of Langerhans cells (LCs), as well as migration of skin dendritic cells (DCs), which the authors confirmed by analysis of Talin1-deficient mouse bone marrow-derived DCs (BMDCs). Further analysis with BMDCs revealed that Talin1 regulated DC activation upon lipopolysaccharide (LPS) stimulation by promoting LPS-induced NFKB (see 164011) activation in DCs. Upstream of NFKB, Talin1 acted as a scaffold protein that was required for preassembly of the Tlr4 (603030) complex with Tirap (606252) and Myd88 (602170) in DCs at steady state. Moreover, Talin1 was required for signalosome assembly upon LPS stimulation and subsequent recruitment and activation of integrins in the preassembled Tlr4 complex in DCs. Talin1 interacted directly with Myd88, and the interaction was mediated by the rod domain of Talin1 and the intermediate domain of Myd88. By interacting with Myd88, Talin1 not only regulated the Tlr4-mediated signaling pathways in DCs, but also other Myd88-dependent TLR signaling pathways in general. Tirap recruitment to the Tlr4 complex for preassembly in DCs at steady state was mediated by phosphatidylinositol 4,5-bisphosphate (PIP2), and production of PIP2 was catalyzed by Pip5k (see 603275). Talin1 interacted with Pip5k to increase local PIP2 concentration in the proximity of TLRs, thereby facilitating recruitment of Tirap to Tlr4 in DCs. Functional analysis in a mouse model of cutaneous bacterial infection indicated that, by regulating DC activation, Talin1 controlled DC-mediated antibacterial immune responses and regulated skin tolerance toward innocuous hapten.
Using magnetic tweezers, total internal reflection fluorescence, and atomic force microscopy, del Rio et al. (2009) investigated the effect of force on the interaction between talin, a protein that links liganded membrane integrins to the cytoskeleton, and vinculin, a focal adhesion protein that is activated by talin binding, leading to reorganization of the cytoskeleton. Application of physiologically relevant forces caused stretching of single talin rods that exposed cryptic binding sites for vinculin. Thus in the talin-vinculin system, molecular mechanotransduction can occur by protein binding after exposure of buried binding sites in the talin-vinculin system.
Using PCR amplification and DNA from a panel of human/rodent somatic cell hybrids, Gilmore et al. (1995) assigned the TLN gene to 9p. Deletions in 9p have been implicated in a variety of cancers. That a cytoskeletal protein associated with the cell adhesion apparatus, such as talin, might behave as a tumor suppressor gene has been proposed. For example, the APC tumor suppressor gene (APC; 611731) encodes a protein that associates with beta-catenin (CTNNB1; 116806), a component of a complex of proteins linked to the cytoplasmic face of the cadherin family of cell-cell adhesion molecules. Similarly, talin is a component of a complex of proteins linked to the cytoplasmic face of integrins in cell-ECM junctions (Luna and Hitt, 1992).
del Rio, A., Perez-Jimenez, R., Liu, R., Roca-Cusachs, P., Fernandez, J. M., Sheetz, M. P. Stretching single talin rod molecules activates vinculin binding. Science 323: 638-641, 2009. [PubMed: 19179532] [Full Text: https://doi.org/10.1126/science.1162912]
Di Paolo, G., Pellegrini, L., Letinic, K., Cestra, G., Zoncu, R., Voronov, S., Chang, S., Guo, J., Wenk, M. R., De Camill, P. Recruitment and regulation of phosphatidylinositol phosphate kinase type I-gamma by the FERM domain of talin. Nature 420: 85-89, 2002. [PubMed: 12422219] [Full Text: https://doi.org/10.1038/nature01147]
Gilmore, A. P., Ohanian, V., Spurr, N. K., Critchley, D. R. Localisation of the human gene encoding the cytoskeletal protein talin to chromosome 9p. Hum. Genet. 96: 221-224, 1995. [PubMed: 7635475] [Full Text: https://doi.org/10.1007/BF00207384]
Hu, K., Ji, L., Applegate, K. T., Danuser, G., Waterman-Storer, C. M. Differential transmission of actin motion within focal adhesions. Science 315: 111-115, 2007. [PubMed: 17204653] [Full Text: https://doi.org/10.1126/science.1135085]
Jiang, G., Giannone, G., Critchley, D. R., Fukumoto, E., Sheetz, M. P. Two-piconewton slip bond between fibronectin and the cytoskeleton depends on talin. Nature 424: 334-337, 2003. [PubMed: 12867986] [Full Text: https://doi.org/10.1038/nature01805]
Kanchanawong, P., Shtengel, G., Pasapera, A. M., Ramko, E. B., Davidson, M. W., Hess, H. F., Waterman, C. M. Nanoscale architecture of integrin-based cell adhesions. Nature 468: 580-584, 2010. [PubMed: 21107430] [Full Text: https://doi.org/10.1038/nature09621]
Lim, T. J. F., Bunjamin, M., Ruedl, C., Su, I. H. Talin1 controls dendritic cell activation by regulating TLR complex assembly and signaling. J. Exp. Med. 217: e20191810, 2020. [PubMed: 32438408] [Full Text: https://doi.org/10.1084/jem.20191810]
Ling, K., Doughman, R. L., Firestone, A. J., Bunce, M. W., Anderson, R. A. Type I-gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions. Nature 420: 89-93, 2002. [PubMed: 12422220] [Full Text: https://doi.org/10.1038/nature01082]
Luna, E. J., Hitt, A. L. Cytoskeleton-plasma membrane interactions. Science 258: 955-964, 1992. [PubMed: 1439807] [Full Text: https://doi.org/10.1126/science.1439807]
Rees, D. J. G., Ades, S. E., Singer, S. J., Hynes, R. O. Sequence and domain structure of talin. Nature 347: 685-689, 1990. [PubMed: 2120593] [Full Text: https://doi.org/10.1038/347685a0]
Shen, B., Zhao, X., O'Brien, K. A., Stojanovic-Terpo, A., Delaney, M. K., Kim, K., Cho, J., Lam, S. C.-T., Du, X. A directional switch of integrin signalling and a new anti-thrombotic strategy. Nature 503: 131-135, 2013. [PubMed: 24162846] [Full Text: https://doi.org/10.1038/nature12613]
Tadokoro, S., Shattil, S. J., Eto, K., Tai, V., Liddington, R. C., de Pereda, J. M., Ginsberg, M. H., Calderwood, D. A. Talin binding to integrin beta tails: a final common step in integrin activation. Science 302: 103-106, 2003. [PubMed: 14526080] [Full Text: https://doi.org/10.1126/science.1086652]