The LIM Protein Ajuba Is Recruited to Cadherin-dependent Cell Junctions through an Association with α-Catenin

Abstract

Cell-cell adhesive events affect cell growth and fate decisions and provide spatial clues for cell polarity within tissues. The complete molecular determinants required for adhesive junction formation and their function are not completely understood. LIM domain-containing proteins have been shown to be present at cellcell contact sites and are known to shuttle into the nucleus where they can affect cell fate and growth; however, their precise localization at cell-cell contacts, how they localize to these sites, and what their functions are at these sites is unknown. Here we show that, in primary keratinocytes, the LIM domain protein Ajuba is recruited to cadherin-dependent cell-cell adhesive complexes in a regulated manner. At cadherin adhesive complexes Ajuba interacts with ␣-catenin, and ␣-catenin is required for efficient recruitment of Ajuba to cell junctions. Ajuba also interacts directly with F-actin. Keratinocytes from Ajuba null mice exhibit abnormal cell-cell junction formation and/or stability and function. These data reveal Ajuba as a new component at cadherin-mediated cell-cell junctions and 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.Cell-to-cell adhesion is important for tissue morphogenesis. During development, cell-cell contacts provide spatial clues for cell polarity and sorting, thereby ensuring proper cellular organization within tissues. Cell surface adhesion receptor proteins direct cell-cell adhesion. The cadherins, for example, are a superfamily of receptors that display calcium-dependent adhesion between the same types of proteins (i.e. homophilic interaction). E-cadherin is one of the best studied cell-cell adhesion proteins. In epithelia, E-cadherin has an important role in the generation and maintenance of the cell morphology, polarity, and function (1, 2).At adhesive contacts, E-cadherin receptors also provide cytosolic actin filaments with points of attachment to the membrane, from which tension and reorganization of the cortical cytoskeleton are initiated. E-cadherin-mediated adhesion triggers redistribution of membrane, cytoskeletal, and cytosolic signaling proteins to sites of cell-cell contacts, giving rise to multiprotein signaling complexes (1). Much investigation has been directed at understanding how these supramolecular protein complexes are formed, what proteins make up the functional complex, and what their contribution is to the strength of junction formation and remodeling of the cytoskeletal network.Proteins of the catenin family indirectly mediate the binding of actin filaments to cadherin receptors. ␤-Catenin (or ␥-catenin/plakoglobin) associates directly with the cadherin tail, and then ␣-catenin bridges the ␤-catenin-cadherin complex to actin filaments (1). ␣-Catenin is an essential component of the cadherin complex (1). It not only binds and bundles actin (3) but also provides docking sites for other cyt...

Ajuba Functions as a Histone Deacetylase-dependent Co-repressor for Autoregulation of the Growth Factor-independent-1 Transcription Factor

“…Tethering fulllength Ajuba alone to DNA did not provide significant transcriptional repression, whereas LexA-Ajuba increased the repression of Gfi1-LexA. Ajuba PreLIM region and LIM domains often interact with distinct proteins that contribute to a common cellular function (7,35). Notably, the LIM domains, when trapped in the nucleus, affect cell proliferation (LIM1 or -2) and differentiation (LIM3), whereas the PreLIM region affects cell proliferation (6).…”

LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling

“…Ajuba functions as a scaffold protein participating in assembly of numerous protein complexes in both cell compartments, and has been found to bind Grb2, TRAF6, the p130Cas/Dock180 Rac guanine nucleotide-exchange factor, α-catenin, F-actin, and Aurora A kinase to regulate multiple cellular activities, including cell adhesion, migration, wound healing, and mitosis (1)(2)(3)(4)(5). In the nucleus, one function of Ajuba is to act as a corepressor for the zinc finger-protein Snail, recruiting Prmt5 to repress Snail target genes and function in the epithelial-mesenchymal transition differentiation process (6)(7)(8).…”

The LIM protein Ajuba promotes adipogenesis by enhancing PPARγ and p300/CBP interaction

“…[16][17][18]22 Ajuba functions as a scaffold involving assembly of multiple protein complexes to regulate cell adhesion, migration, mitosis, microRNA maturation, cell differentiation and tissue development. [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Ajuba can directly participate in transcriptional regulation where it serves as a transcriptional co-repressor and downregulate gene expression. We lately identified Ajuba as a co-repressor for Snail and as an essential regulator of mesenchymal-epithelial transition and metastasis.…”