Abstract
Loss of function mutations in the nuclear inner membrane protein, emerin, cause X-linked Emery-Dreifuss muscular dystrophy (X-EDMD). X-EDMD is characterized by contractures of major tendons, skeletal muscle weakening and wasting, and cardiac conduction system defects. The transcription factor Lmo7 regulates muscle- and heart-relevant genes and is inhibited by binding to emerin, suggesting Lmo7 misregulation contributes to EDMD disease. Lmo7 associates with cell adhesions and shuttles between the plasma membrane and nucleus, but the regulation and biological consequences of this dual localization were unknown. We report endogenous Lmo7 also associates with focal adhesions in cells, and both co-localizes and co-immunoprecipitates with p130Cas, a key signaling component of focal adhesions. Lmo7 nuclear localization and transcriptional activity increased significantly in p130Cas-null MEFs, suggesting Lmo7 is negatively regulated by p130Cas-dependent association with focal adhesions. These results support EDMD models in which Lmo7 is a downstream mediator of integrin-dependent signaling that allows tendon cells and muscles to adapt to and withstand mechanical stress.
Highlights
Lim domain only 7 (Lmo7) is a transcription factor with major roles in muscle, heart and other tissues (Ott et al, 2008) including lung epithelium, where Lmo7 is proposed to function as a tumor suppressor (Ott et al, 2008; Tanaka-Okamoto et al, 2009)
We report that endogenous Lmo7 associated with focal adhesions in both HeLa cells and mouse embryonic fibroblasts (MEFs), and co-immunoprecipitated with p130Cas, a major scaffolding and signaling component of focal adhesions (Defilippi, Di Stefano & Cabodi, 2006) that influences myogenic differentiation (Kawauchi et al, 2012)
Lmo7 localized at pFAK- and vinculin-positive focal adhesion sites (Figs. 1A and 1B), and at structures near the cell surface that resembled actin stress fibers (Fig. 1B)
Summary
Lim domain only 7 (Lmo7) is a transcription factor with major roles in muscle, heart and other tissues (Ott et al, 2008) including lung epithelium, where Lmo is proposed to function as a tumor suppressor (Ott et al, 2008; Tanaka-Okamoto et al, 2009). Lmo shuttles into and out of the nucleus (Holaska, Rais-Bahrami & Wilson, 2006), and positively regulates many muscle- and heart-relevant genes (Holaska, Rais-Bahrami & Wilson, 2006; Ott et al, 2008). Among these genes is EMD which encodes a conserved nuclear membrane protein named emerin (Berk, Tifft & Wilson, 2013). In cells subjected to external mechanical force, emerin is required to activate specific ‘mechano-sensitive’ genes in response to force (Lammerding et al, 2005)
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