TLN2

Talin 2 is a protein in humans that is encoded by the TLN2 gene. It belongs to the talin protein family. This gene encodes a protein related to talin 1, a cytoskeletal protein that plays a significant role in the assembly of actin filaments. Talin-2 is expressed at high levels in cardiac muscle and functions to provide linkages between the extracellular matrix and actin cytoskeleton at costamere structures to transduce force laterally.[5]

TLN2
Identifiers
Aliases	TLN2, ILWEQ, talin 2
External IDs	OMIM: 607349 MGI: 1917799 HomoloGene: 56692 GeneCards: TLN2
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q22.2 Start 62,390,526 bp[1] End 62,844,631 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9|9 C Start 67,217,087 bp[2] End 67,559,703 bp[2]
Gene ontology Molecular function • actin binding • actin filament binding • structural constituent of cytoskeleton • GO:0001948 protein binding • structural molecule activity Cellular component • cytoplasm • ruffle • cell junction • cell membrane • synapse • cytoskeleton • membrane • intercellular junction • focal adhesion • actin cytoskeleton Biological process • cell adhesion • cell-cell junction assembly Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	83660	70549
Ensembl	ENSG00000171914	ENSMUSG00000052698
UniProt	Q9Y4G6	Q71LX4
RefSeq (mRNA)	NM_015059	NM_001081242 NM_027458
RefSeq (protein)	NP_055874	NP_001074711
Location (UCSC)	Chr 15: 62.39 – 62.84 Mb	Chr 9: 67.22 – 67.56 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Human talin-2 is 271.4 kDa and 2542 amino acids in length.[6] The size of talin-2 protein is similar to talin-1, and is relatively similar (74% identity, 86% similarity); the size of the talin-2 gene (200 kb) is however much larger than that of talin-1 (30 kb), due to differences in intron sizes.[7] Talin-2 mRNA is expressed in multiple tissues, including cardiac muscle, mouse embryonic stem cells, brain, lung, skeletal muscle, kidney and testis; however expression is highest in cardiac muscle.[7][8][9][10] A detailed analysis of the TLN2 gene revealed that the alternative splicing of TLN2 is complex and encodes multiple mRNA transcripts and protein isoforms. Studies revealed a promoter associated with a CpG island that accounts for most of the TLN2 expression in adult tissues. This promoter is separated from the first coding exon by approximately > 200 kb of alternatively spliced noncoding exons. The testis and kidney talin-2 isoforms lack the N-terminal 50% of the protein, and evidence suggests that this is the isoform expressed in elongating spermatids.[11] Talin is also post-translationally modified via calpain 2-mediated cleavage, which may target it for ubiquitin-proteasome-mediated degradation and turnover of associated cell adhesion structures.[12]

Function

The expression of talin-2 in striated muscle is developmentally regulated. Undifferentiated myoblasts primarily express talin-1, and both mRNA and protein expression of talin-2 is upregulated during differentiation; ectopic expression of talin-2 in undifferentiated myoblasts dysregulates the actin cytoskeleton, demonstrating that the timing of talin-2 expression during development is critical. In mature cardiomyocytes and skeletal muscle, talin-2 is expressed at costameres and intercalated discs, thus demonstrating that talin2 links integrins and the actin cytoskeleton in stable adhesion complexes involving mature sarcomeres.[10][13] Talin-2 appears to play a role in skeletal muscle development; specifically, in myoblast fusion, sarcomere assembly, and the integrity of myotendinous junctions. Ablation of both talin isoforms, talin-2 and talin-1 prevented normal myoblast fusion and sarcomere assembly, as well as assembly of integrin adhesion complexes, which was attributed to disrupted interactions between integrins and the actin cytoskeleton.[14] The mRNA expression of talin-2 has been shown to be regulated by the muscle-specific fragile X mental retardation, autosomal homolog 1 (FXR1) protein, which binds talin2 mRNAs directly and represses translation. Knockout of FXR1 upregulates talin-2 protein, which disrupts the architecture of desmosomes and costameres in cardiac muscle.[15]

Talin-2, like talin-1 appears to join ligand-bound integrins and the actin cytoskeleton, which enhances the affinity of integrins for the extracellular matrix and catalyzes focal adhesion-dependent signaling pathways,[16] as well as reinforces the cytoskeletal-integrin structure in response to an applied force.[17] The strength of the interaction between talin and integrin appears to be fine-tuned through differential expression of isoforms in different tissues. The talin-2/β1D-integrin isoforms that are expressed and colocalize in striated muscle form a markedly strong interaction, and a few amino acid deletions in the β1-integrin tail can alter this interaction by 1000-fold.[18]

Talin-2 is found within the neuronal synaptic region in brain tissue, and plays a role in clathrin-mediated endocytosis, coordinating phosphatidylinositol synthesis, and modulating actin dynamics through interactions with PIP kinase type 1γ, the major phosphatidylinositol 4,5-bisphosphate-synthesizing enzyme of the brain.[19]

Clinical significance

In patients with temporal lobe epilepsy, talin-2 protein was detected in cerebrospinal fluid, whereas expression was absent in non-epileptic patients.[20] Furthermore, postencephalitic epilepsy patients that were refractory to drug treatment exhibited markedly elevated levels of talin-2 protein in cerebrospinal fluid and reciprocally decreased levels in serum.[21] These data suggest that talin-2 may prove useful as a biomarker for epilepsy, and may be pathologically linked to this disease.

Studies have also shown that TLN2 is a direct target of miR-132, which is epigenetically silenced in prostate cancer,[22] suggesting that talin-2 may play a role in modulating cell adhesion in prostate cancer.

Interactions

TLN2 has been shown to interact with:

• ACTA1,[23]
• CD61,[24][25]
• ITGB1,[26]
• LAYN,[27][28]
• PTK2,[29][30]

References

1. GRCh38: Ensembl release 89: ENSG00000171914 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000052698 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: Talin 2".
6. "Protein sequence of human TLN2 (Uniprot ID: Q9Y4G6)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Retrieved 8 July 2015.
7. Monkley SJ, Pritchard CA, Critchley DR (Sep 2001). "Analysis of the mammalian talin2 gene TLN2". Biochemical and Biophysical Research Communications. 286 (5): 880–5. doi:10.1006/bbrc.2001.5497. PMID 11527381.
8. Praekelt U, Kopp PM, Rehm K, Linder S, Bate N, Patel B, Debrand E, Manso AM, Ross RS, Conti F, Zhang MZ, Harris RC, Zent R, Critchley DR, Monkley SJ (Mar 2012). "New isoform-specific monoclonal antibodies reveal different sub-cellular localisations for talin1 and talin2". European Journal of Cell Biology. 91 (3): 180–91. doi:10.1016/j.ejcb.2011.12.003. PMC 3629562. PMID 22306379.
9. Chen NT, Lo SH (Nov 2005). "The N-terminal half of talin2 is sufficient for mouse development and survival". Biochemical and Biophysical Research Communications. 337 (2): 670–6. doi:10.1016/j.bbrc.2005.09.100. PMID 16202389.
10. Senetar MA, Moncman CL, McCann RO (Mar 2007). "Talin2 is induced during striated muscle differentiation and is targeted to stable adhesion complexes in mature muscle". Cell Motility and the Cytoskeleton. 64 (3): 157–73. doi:10.1002/cm.20173. PMID 17183545.
11. Debrand E, El Jai Y, Spence L, Bate N, Praekelt U, Pritchard CA, Monkley SJ, Critchley DR (Mar 2009). "Talin 2 is a large and complex gene encoding multiple transcripts and protein isoforms". The FEBS Journal. 276 (6): 1610–28. doi:10.1111/j.1742-4658.2009.06893.x. PMC 2702505. PMID 19220457.
12. Bate N, Gingras AR, Bachir A, Horwitz R, Ye F, Patel B, Goult BT, Critchley DR (2012). "Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics". PLOS ONE. 7 (4): e34461. doi:10.1371/journal.pone.0034461. PMC 3319578. PMID 22496808.
13. Manso AM, Li R, Monkley SJ, Cruz NM, Ong S, Lao DH, Koshman YE, Gu Y, Peterson KL, Chen J, Abel ED, Samarel AM, Critchley DR, Ross RS (Feb 2013). "Talin1 has unique expression versus talin 2 in the heart and modifies the hypertrophic response to pressure overload". The Journal of Biological Chemistry. 288 (6): 4252–64. doi:10.1074/jbc.M112.427484. PMC 3567677. PMID 23266827.
14. Conti FJ, Monkley SJ, Wood MR, Critchley DR, Müller U (Nov 2009). "Talin 1 and 2 are required for myoblast fusion, sarcomere assembly and the maintenance of myotendinous junctions". Development. 136 (21): 3597–606. doi:10.1242/dev.035857. PMC 2761109. PMID 19793892.
15. Whitman SA, Cover C, Yu L, Nelson DL, Zarnescu DC, Gregorio CC (Jul 2011). "Desmoplakin and talin2 are novel mRNA targets of fragile X-related protein-1 in cardiac muscle". Circulation Research. 109 (3): 262–71. doi:10.1161/CIRCRESAHA.111.244244. PMC 3163600. PMID 21659647.
16. Zhang X, Jiang G, Cai Y, Monkley SJ, Critchley DR, Sheetz MP (Sep 2008). "Talin depletion reveals independence of initial cell spreading from integrin activation and traction". Nature Cell Biology. 10 (9): 1062–8. doi:10.1038/ncb1765. PMC 2746969. PMID 19160486.
17. Roca-Cusachs P, Gauthier NC, Del Rio A, Sheetz MP (Sep 2009). "Clustering of alpha(5)beta(1) integrins determines adhesion strength whereas alpha(v)beta(3) and talin enable mechanotransduction". Proceedings of the National Academy of Sciences of the United States of America. 106 (38): 16245–50. doi:10.1073/pnas.0902818106. PMC 2752568. PMID 19805288.
18. Anthis NJ, Wegener KL, Critchley DR, Campbell ID (Dec 2010). "Structural diversity in integrin/talin interactions". Structure. 18 (12): 1654–66. doi:10.1016/j.str.2010.09.018. PMC 3157975. PMID 21134644.
19. Morgan JR, Di Paolo G, Werner H, Shchedrina VA, Pypaert M, Pieribone VA, De Camilli P (Oct 2004). "A role for talin in presynaptic function". The Journal of Cell Biology. 167 (1): 43–50. doi:10.1083/jcb.200406020. PMC 2172527. PMID 15479735.
20. Xiao F, Chen D, Lu Y, Xiao Z, Guan LF, Yuan J, Wang L, Xi ZQ, Wang XF (Feb 2009). "Proteomic analysis of cerebrospinal fluid from patients with idiopathic temporal lobe epilepsy". Brain Research. 1255: 180–9. doi:10.1016/j.brainres.2008.12.008. PMID 19109932.
21. Xiao Z, Shen L, Chen D, Wang L, Xi Z, Xiao F, Wang X (Sep 2010). "Talin 2 concentrations in cerebrospinal fluid in patients with epilepsy". Clinical Biochemistry. 43 (13–14): 1129–32. doi:10.1016/j.clinbiochem.2010.06.015. PMID 20620133.
22. Formosa A, Lena AM, Markert EK, Cortelli S, Miano R, Mauriello A, Croce N, Vandesompele J, Mestdagh P, Finazzi-Agrò E, Levine AJ, Melino G, Bernardini S, Candi E (Jan 2013). "DNA methylation silences miR-132 in prostate cancer". Oncogene. 32 (1): 127–34. doi:10.1038/onc.2012.14. PMID 22310291.
23. Hemmings L, Rees DJ, Ohanian V, Bolton SJ, Gilmore AP, Patel B, Priddle H, Trevithick JE, Hynes RO, Critchley DR (Nov 1996). "Talin contains three actin-binding sites each of which is adjacent to a vinculin-binding site". Journal of Cell Science. 109 (11): 2715–26. PMID 8937989.
24. Patil S, Jedsadayanmata A, Wencel-Drake JD, Wang W, Knezevic I, Lam SC (Oct 1999). "Identification of a talin-binding site in the integrin beta(3) subunit distinct from the NPLY regulatory motif of post-ligand binding functions. The talin n-terminal head domain interacts with the membrane-proximal region of the beta(3) cytoplasmic tail". The Journal of Biological Chemistry. 274 (40): 28575–83. doi:10.1074/jbc.274.40.28575. PMID 10497223.
25. Calderwood DA, Yan B, de Pereda JM, Alvarez BG, Fujioka Y, Liddington RC, Ginsberg MH (Jun 2002). "The phosphotyrosine binding-like domain of talin activates integrins". The Journal of Biological Chemistry. 277 (24): 21749–58. doi:10.1074/jbc.M111996200. PMID 11932255.
26. Calderwood DA, Zent R, Grant R, Rees DJ, Hynes RO, Ginsberg MH (Oct 1999). "The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation". The Journal of Biological Chemistry. 274 (40): 28071–4. doi:10.1074/jbc.274.40.28071. PMID 10497155.
27. Borowsky ML, Hynes RO (Oct 1998). "Layilin, a novel talin-binding transmembrane protein homologous with C-type lectins, is localized in membrane ruffles". The Journal of Cell Biology. 143 (2): 429–42. doi:10.1083/jcb.143.2.429. PMC 2132847. PMID 9786953.
28. Wegener KL, Basran J, Bagshaw CR, Campbell ID, Roberts GC, Critchley DR, Barsukov IL (Sep 2008). "Structural basis for the interaction between the cytoplasmic domain of the hyaluronate receptor layilin and the talin F3 subdomain". Journal of Molecular Biology. 382 (1): 112–26. doi:10.1016/j.jmb.2008.06.087. PMID 18638481.
29. Chen HC, Appeddu PA, Parsons JT, Hildebrand JD, Schaller MD, Guan JL (Jul 1995). "Interaction of focal adhesion kinase with cytoskeletal protein talin". The Journal of Biological Chemistry. 270 (28): 16995–9. doi:10.1074/jbc.270.28.16995. PMID 7622520.
30. Zheng C, Xing Z, Bian ZC, Guo C, Akbay A, Warner L, Guan JL (Jan 1998). "Differential regulation of Pyk2 and focal adhesion kinase (FAK). The C-terminal domain of FAK confers response to cell adhesion". The Journal of Biological Chemistry. 273 (4): 2384–9. doi:10.1074/jbc.273.4.2384. PMID 9442086.

Further reading

• Anthis NJ, Wegener KL, Critchley DR, Campbell ID (Dec 2010). "Structural diversity in integrin/talin interactions". Structure. 18 (12): 1654–66. doi:10.1016/j.str.2010.09.018. PMC 3157975. PMID 21134644.
• Shoeman RL, Hartig R, Hauses C, Traub P (2002). "Organization of focal adhesion plaques is disrupted by action of the HIV-1 protease". Cell Biology International. 26 (6): 529–39. doi:10.1006/cbir.2002.0895. PMID 12119179.
• Critchley DR, Holt MR, Barry ST, Priddle H, Hemmings L, Norman J (1999). "Integrin-mediated cell adhesion: the cytoskeletal connection". Biochemical Society Symposium. 65: 79–99. PMID 10320934.
• Di Paolo G, Pellegrini L, Letinic K, Cestra G, Zoncu R, Voronov S, Chang S, Guo J, Wenk MR, De Camilli P (Nov 2002). "Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin". Nature. 420 (6911): 85–9. doi:10.1038/nature01147. PMID 12422219.
• Zemljic-Harpf A, Manso AM, Ross RS (Dec 2009). "Vinculin and talin: focus on the myocardium". Journal of Investigative Medicine. 57 (8): 849–55. doi:10.2310/jim.0b013e3181c5e074. PMC 2810504. PMID 19952892.
• Ling K, Doughman RL, Firestone AJ, Bunce MW, Anderson RA (Nov 2002). "Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions". Nature. 420 (6911): 89–93. doi:10.1038/nature01082. PMID 12422220.
• Xiao F, Chen D, Lu Y, Xiao Z, Guan LF, Yuan J, Wang L, Xi ZQ, Wang XF (Feb 2009). "Proteomic analysis of cerebrospinal fluid from patients with idiopathic temporal lobe epilepsy". Brain Research. 1255: 180–9. doi:10.1016/j.brainres.2008.12.008. PMID 19109932.
• Critchley DR (Nov 2004). "Cytoskeletal proteins talin and vinculin in integrin-mediated adhesion". Biochemical Society Transactions. 32 (Pt 5): 831–6. doi:10.1042/BST0320831. PMID 15494027.
• Vyas YM, Maniar H, Dupont B (Apr 2002). "Cutting edge: differential segregation of the SRC homology 2-containing protein tyrosine phosphatase-1 within the early NK cell immune synapse distinguishes noncytolytic from cytolytic interactions". Journal of Immunology. 168 (7): 3150–4. doi:10.4049/jimmunol.168.7.3150. PMID 11907066.