TLN2

{{Short description|Protein-coding gene in the species Homo sapiens}}

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.{{cite web | title = Entrez Gene: Talin 2 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=83660 }}

Structure

Human talin-2 is 271.4 kDa and 2542 amino acids in length.{{cite web|title=Protein sequence of human TLN2 (Uniprot ID: Q9Y4G6)|url=http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q9Y4G6|website=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)|access-date=8 July 2015|archive-date=9 July 2015|archive-url=https://web.archive.org/web/20150709130652/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q9Y4G6|url-status=dead}} 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.{{cite journal | vauthors = Monkley SJ, Pritchard CA, Critchley DR | title = Analysis of the mammalian talin2 gene TLN2 | journal = Biochemical and Biophysical Research Communications | volume = 286 | issue = 5 | pages = 880–5 | date = Sep 2001 | pmid = 11527381 | doi = 10.1006/bbrc.2001.5497 }} 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.{{cite journal | vauthors = 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 | title = New isoform-specific monoclonal antibodies reveal different sub-cellular localisations for talin1 and talin2 | journal = European Journal of Cell Biology | volume = 91 | issue = 3 | pages = 180–91 | date = Mar 2012 | pmid = 22306379 | doi = 10.1016/j.ejcb.2011.12.003 | pmc=3629562}}{{cite journal | vauthors = Chen NT, Lo SH | title = The N-terminal half of talin2 is sufficient for mouse development and survival | journal = Biochemical and Biophysical Research Communications | volume = 337 | issue = 2 | pages = 670–6 | date = Nov 2005 | pmid = 16202389 | doi = 10.1016/j.bbrc.2005.09.100 }}{{cite journal | vauthors = Senetar MA, Moncman CL, McCann RO | title = Talin2 is induced during striated muscle differentiation and is targeted to stable adhesion complexes in mature muscle | journal = Cell Motility and the Cytoskeleton | volume = 64 | issue = 3 | pages = 157–73 | date = Mar 2007 | pmid = 17183545 | doi = 10.1002/cm.20173 }} 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.{{cite journal | vauthors = Debrand E, El Jai Y, Spence L, Bate N, Praekelt U, Pritchard CA, Monkley SJ, Critchley DR | title = Talin 2 is a large and complex gene encoding multiple transcripts and protein isoforms | journal = The FEBS Journal | volume = 276 | issue = 6 | pages = 1610–28 | date = Mar 2009 | pmid = 19220457 | doi = 10.1111/j.1742-4658.2009.06893.x | pmc=2702505}} 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.{{cite journal | vauthors = Bate N, Gingras AR, Bachir A, Horwitz R, Ye F, Patel B, Goult BT, Critchley DR | title = Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics | journal = PLOS ONE | volume = 7 | issue = 4 | pages = e34461 | date = 2012 | pmid = 22496808 | doi = 10.1371/journal.pone.0034461 | pmc=3319578| bibcode = 2012PLoSO...734461B | doi-access = free }}

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.{{cite journal | vauthors = 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 | title = Talin1 has unique expression versus talin 2 in the heart and modifies the hypertrophic response to pressure overload | journal = The Journal of Biological Chemistry | volume = 288 | issue = 6 | pages = 4252–64 | date = Feb 2013 | pmid = 23266827 | doi = 10.1074/jbc.M112.427484 | pmc=3567677| doi-access = free }} 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.{{cite journal | vauthors = Conti FJ, Monkley SJ, Wood MR, Critchley DR, Müller U | title = Talin 1 and 2 are required for myoblast fusion, sarcomere assembly and the maintenance of myotendinous junctions | journal = Development | volume = 136 | issue = 21 | pages = 3597–606 | date = Nov 2009 | pmid = 19793892 | doi = 10.1242/dev.035857 | pmc=2761109}} 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.{{cite journal | vauthors = Whitman SA, Cover C, Yu L, Nelson DL, Zarnescu DC, Gregorio CC | title = Desmoplakin and talin2 are novel mRNA targets of fragile X-related protein-1 in cardiac muscle | journal = Circulation Research | volume = 109 | issue = 3 | pages = 262–71 | date = Jul 2011 | pmid = 21659647 | doi = 10.1161/CIRCRESAHA.111.244244 | pmc=3163600}}

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,{{cite journal | vauthors = Zhang X, Jiang G, Cai Y, Monkley SJ, Critchley DR, Sheetz MP | title = Talin depletion reveals independence of initial cell spreading from integrin activation and traction | journal = Nature Cell Biology | volume = 10 | issue = 9 | pages = 1062–8 | date = Sep 2008 | pmid = 19160486 | doi = 10.1038/ncb1765 | pmc=2746969}} as well as reinforces the cytoskeletal-integrin structure in response to an applied force.{{cite journal | vauthors = Roca-Cusachs P, Gauthier NC, Del Rio A, Sheetz MP | title = Clustering of alpha(5)beta(1) integrins determines adhesion strength whereas alpha(v)beta(3) and talin enable mechanotransduction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 38 | pages = 16245–50 | date = Sep 2009 | pmid = 19805288 | doi = 10.1073/pnas.0902818106 | pmc=2752568| doi-access = free }} 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.{{cite journal | vauthors = Anthis NJ, Wegener KL, Critchley DR, Campbell ID | title = Structural diversity in integrin/talin interactions | journal = Structure | volume = 18 | issue = 12 | pages = 1654–66 | date = Dec 2010 | pmid = 21134644 | doi = 10.1016/j.str.2010.09.018 | pmc=3157975}}

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.{{cite journal | vauthors = Morgan JR, Di Paolo G, Werner H, Shchedrina VA, Pypaert M, Pieribone VA, De Camilli P | title = A role for talin in presynaptic function | journal = The Journal of Cell Biology | volume = 167 | issue = 1 | pages = 43–50 | date = Oct 2004 | pmid = 15479735 | doi = 10.1083/jcb.200406020 | pmc=2172527}}

Clinical significance

In patients with temporal lobe epilepsy, talin-2 protein was detected in cerebrospinal fluid, whereas expression was absent in non-epileptic patients.{{cite journal | vauthors = Xiao F, Chen D, Lu Y, Xiao Z, Guan LF, Yuan J, Wang L, Xi ZQ, Wang XF | title = Proteomic analysis of cerebrospinal fluid from patients with idiopathic temporal lobe epilepsy | journal = Brain Research | volume = 1255 | pages = 180–9 | date = Feb 2009 | pmid = 19109932 | doi = 10.1016/j.brainres.2008.12.008 | s2cid = 41644337 }} 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.{{cite journal | vauthors = Xiao Z, Shen L, Chen D, Wang L, Xi Z, Xiao F, Wang X | title = Talin 2 concentrations in cerebrospinal fluid in patients with epilepsy | journal = Clinical Biochemistry | volume = 43 | issue = 13–14 | pages = 1129–32 | date = Sep 2010 | pmid = 20620133 | doi = 10.1016/j.clinbiochem.2010.06.015 }} 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,{{cite journal | vauthors = 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 | title = DNA methylation silences miR-132 in prostate cancer | journal = Oncogene | volume = 32 | issue = 1 | pages = 127–34 | date = Jan 2013 | pmid = 22310291 | doi = 10.1038/onc.2012.14 | doi-access = free }} suggesting that talin-2 may play a role in modulating cell adhesion in prostate cancer.

Interactions

TLN2 has been shown to interact with:

ACTA1,{{cite journal | vauthors = Hemmings L, Rees DJ, Ohanian V, Bolton SJ, Gilmore AP, Patel B, Priddle H, Trevithick JE, Hynes RO, Critchley DR | title = Talin contains three actin-binding sites each of which is adjacent to a vinculin-binding site | journal = Journal of Cell Science | volume = 109 | pages = 2715–26 | date = Nov 1996 | pmid = 8937989 | issue=11| doi = 10.1242/jcs.109.11.2715 | url = https://figshare.com/articles/journal_contribution/10165394 | hdl = 2381/38298 | hdl-access = free }}
CD61,{{cite journal | vauthors = Patil S, Jedsadayanmata A, Wencel-Drake JD, Wang W, Knezevic I, Lam SC | title = 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 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 40 | pages = 28575–83 | date = Oct 1999 | pmid = 10497223 | doi=10.1074/jbc.274.40.28575| doi-access = free }}{{cite journal | vauthors = Calderwood DA, Yan B, de Pereda JM, Alvarez BG, Fujioka Y, Liddington RC, Ginsberg MH | title = The phosphotyrosine binding-like domain of talin activates integrins | journal = The Journal of Biological Chemistry | volume = 277 | issue = 24 | pages = 21749–58 | date = Jun 2002 | pmid = 11932255 | doi = 10.1074/jbc.M111996200 | doi-access = free }}
ITGB1,{{cite journal | vauthors = Calderwood DA, Zent R, Grant R, Rees DJ, Hynes RO, Ginsberg MH | title = The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation | journal = The Journal of Biological Chemistry | volume = 274 | issue = 40 | pages = 28071–4 | date = Oct 1999 | pmid = 10497155 | doi=10.1074/jbc.274.40.28071| doi-access = free }}
LAYN,{{cite journal | vauthors = Borowsky ML, Hynes RO | title = Layilin, a novel talin-binding transmembrane protein homologous with C-type lectins, is localized in membrane ruffles | journal = The Journal of Cell Biology | volume = 143 | issue = 2 | pages = 429–42 | date = Oct 1998 | pmid = 9786953 | doi=10.1083/jcb.143.2.429 | pmc=2132847}}{{cite journal | vauthors = Wegener KL, Basran J, Bagshaw CR, Campbell ID, Roberts GC, Critchley DR, Barsukov IL | title = Structural basis for the interaction between the cytoplasmic domain of the hyaluronate receptor layilin and the talin F3 subdomain | journal = Journal of Molecular Biology | volume = 382 | issue = 1 | pages = 112–26 | date = Sep 2008 | pmid = 18638481 | doi = 10.1016/j.jmb.2008.06.087 }}
PTK2,{{cite journal | vauthors = Chen HC, Appeddu PA, Parsons JT, Hildebrand JD, Schaller MD, Guan JL | title = Interaction of focal adhesion kinase with cytoskeletal protein talin | journal = The Journal of Biological Chemistry | volume = 270 | issue = 28 | pages = 16995–9 | date = Jul 1995 | pmid = 7622520 | doi = 10.1074/jbc.270.28.16995 | doi-access = free }}{{cite journal | vauthors = Zheng C, Xing Z, Bian ZC, Guo C, Akbay A, Warner L, Guan JL | title = Differential regulation of Pyk2 and focal adhesion kinase (FAK). The C-terminal domain of FAK confers response to cell adhesion | journal = The Journal of Biological Chemistry | volume = 273 | issue = 4 | pages = 2384–9 | date = Jan 1998 | pmid = 9442086 | doi=10.1074/jbc.273.4.2384| doi-access = free }}

TLN2

Structure

Function

Clinical significance

Interactions

References

Further reading