Talin is cut out for intercellular adhesion

Talin is cut out for intercellular adhesion T he cytoskeletal adaptor protein talin helps cells attach to the ex-tracellular matrix by linking actin fi laments to integrin-based focal adhesions. Zhang et al. demonstrate that a pro-teolytic fragment of talin also promotes the formation of intercellular adhesions and that the generation and function of this fragment is regulated by arginylation (1). The enzyme arginyltransferase, or Ate1, transfers arginine from tRNAs onto the N-terminal amino group of target proteins. Arginylation was fi rst described in 1963 (2), but the process has remained in the shadows of better-studied protein mod-ifi cations like phosphorylation and ubiq-uitination. Its relative obscurity doesn't refl ect a lack of importance—Ate1 is essential for the survival of fl ies and mice (3). Nor does it refl ect the modifi cation's prevalence. " Probably at least a quarter of the proteome is arginylated at some point, " estimates Anna Kashina, from the University of Pennsylvania in Philadelphia, who found that talin was arginylated in a large-scale analysis of Ate1 targets (4). " The only target to be somewhat understood mechanistically is ␤-actin, " continues Kashina. " Its arginylation is essential for forming the leading edge of loco-moting cells. " As well as having motility defects, however, Ate1-defi cient cells have problems adhering to the ex-tracellular matrix (5). Kashina and colleagues, led by postdoc Fangliang Zhang (who now runs his own lab at the University of Miami), therefore decided to investigate how arginyla-tion affects the function of talin (1). Talin is arginylated on an alanine residue in its C-terminal tail, suggesting that the protein must fi rst be cleaved at this residue to expose its amino group to Ate1. Accordingly, Zhang et al. found that a C-terminal talin fragment of the predicted size—70 kD—was generated in fi broblasts. Depleting or inhibiting calpain 2—a pro-tease known to cleave other sites in talin— blocked production of the fragment, which the researchers named VAD because it contains talin's vinculin-binding, actin-binding, and dimerization sites. " We expected to fi nd that [the VAD fragment] regulates cells' attachments to the substrate, " Kashina admits. " But, to our surprise, we found that it regulates cell–cell adhesion instead. " VAD colocalized with the adhesion molecule cadherin at intercel-lular junctions, and the fragment's production was enhanced in confl uent fi broblast monolayers making numerous cell–cell contacts. VAD was absent from cells lacking Ate1, on the other hand, which …