The role of the LIM protein, Ajuba in cell adhesion and motility

A cell's ability to adhere to the substratum and to other cells is a highly regulated process that is critical during development and often disrupted in disease states. Cell-cell adhesive events affect cell growth and fate decisions and provide spatial clues for cell polarity within tissues. Cell motility requires the coordinated formation and turnover of adhesions to the substratum, as well as the generation of forces to move the cell forward. LIM domain containing proteins are often found at sites of cell adhesion and have been implicated in regulating adhesion. Here, I report on the role of the LIM protein, Ajuba in cell adhesion and motility.;In primary keratinocytes, Ajuba is recruited to cadherin-dependent cell-cell adhesive complexes in a regulated manner. alpha-catenin mediates the recruitment of Ajuba to adhesive complexes via a direct interaction. Ajuba also interacts directly with F-actin. Keratinocytes from Ajuba null mice exhibit abnormal cell-cell junction formation and/or stability. These data suggest that Ajuba may contribute to the bridging of the cadherin adhesive complexes to the actin cytoskeleton and as such contribute to the formation or strengthening of cadherin-mediated cell-cell adhesion.;The adapter protein p130Cas plays an important role in focal adhesion formation and cell migration through their activation of the small GTPase Rac. Primary fibroblasts from Ajuba null mice show a reduction in migration, without any abnormality in ECM adhesion, cell spreading, or Integrin activation. Ajuba null cells make less total lamellipodia and biochemical analysis of isolated lamellipodia show a marked reduction in a subset of focal complex/adhesion proteins. In addition, the activity of FAK, Crk and p130Cas are reduced in lamellipodia of Ajuba null cells. Rac activation downstream of p130Cas is reduced at the leading edge of Ajuba null cells, as detected biochemically following wounding and by FRET analysis. p130Cas colocalizes with Ajuba at de novo focal complexes/adhesions, interacts with Ajuba in cells, and its overexpression is able to rescue the migration defect in Ajuba null cells. These results suggest that Ajuba is a new and important regulator of cell migration through the recruitment of the p130Cas/DOCK180-signaling complex to the leading edge of lamellipodia of migrating cells.