Ajuba, a Cytosolic LIM Protein, Shuttles into the Nucleus and Affects Embryonal Cell Proliferation and Fate Decisions

Abstract

Cellular adhesive events affect cell proliferation and differentiation decisions. How cell surface events mediating adhesion transduce signals to the nucleus is not well understood. After cell-cell or cell-substratum contact, cytosolic proteins are recruited to clustered adhesion receptor complexes. One such family of cytosolic proteins found at sites of cell adhesion is the Zyxin family of LIM proteins. Here we demonstrate that the family member Ajuba was recruited to the cell surface of embryonal cells, upon aggregate formation, at sites of cell-cell contact. Ajuba contained a functional nuclear export signal and shuttled into the nucleus. Importantly, accumulation of the LIM domains of Ajuba in the nucleus of P19 embryonal cells resulted in growth inhibition and spontaneous endodermal differentiation. The differentiating effect of Ajuba mapped to the third LIM domain, whereas regulation of proliferation mapped to the first and second LIM domains. Ajuba-induced endodermal differentiation of these cells correlated with the capacity to activate c-Jun kinase and required c-Jun kinase activation. These results suggest that the cytosolic LIM protein Ajuba may provide a new mechanism to transduce signals from sites of cell adhesion to the nucleus, regulating cell growth and differentiation decisions during early development.

MicroRNAs direct rapid deadenylation of mRNA

“…Ajuba is a LIM-domain protein that plays an important role in controlling the entry of vertebrate cells into mitosis and meiosis (20,21). In P19 cells induced to differentiate, the concentration of this protein initially rises and then declines (22), suggesting a delayed-onset repression mechanism to which miR-125b may contribute as it accumulates over time. Like lin-28 miRE1, the Ajuba A1 element was found to direct rapid deadenylation and subsequent decay of a reporter mRNA in transfected 293T cells that produced miR-125b (Fig.…”

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

“…Retinoic acid triggers F9 and P19 embryonic stem cells to differentiate into endoderm-like cells and induces the synthesis of TROMA-1 (10,16). In cell culture, low doses of atRA induce P19 cells to differentiate along the endodermal lineage, whereas at higher concentrations atRA induces terminal neuroectodermal differentiation (16).…”

“…Previous studies demonstrated that Ajuba plays a significant role in the regulation of mouse embryonic carcinoma P19 cell proliferation and differentiation, a process highly dependent upon retinoids (10). In cell culture, the addition of alltrans retinoic acid (atRA) to P19 cells results in growth inhibition and differentiation.…”

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

“…289-297) and deletion of the nucleus exporting signal or the whole preLIM region will result in the nucleus accumulation of Ajuba. 16,19 In addition, the preLIM region also mediates the protein-protein interaction, such as HDACs and Prmt5. 20,21 Depending on cell types, Ajuba can be located near the membrane, in the cytoplasm and/or in the nucleus and the stimulation of signals or interaction with proteins will also change its localization in cells.…”

“…[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.…”