Emerging Mechanobiological Roles of LIM ‐Only Proteins: Distinct Pathways of CRP and LMO in Cytoskeleton Regulation and Disease

Mechanotransduction is a process in which cells sense extracellular cues from their microenvironment and convert mechanical changes into biochemical signals, thereby regulating gene expression and various cellular processes. LIM-domain proteins have recently been identified as essential players in several mechanotransduction pathways. They have been shown to bind tensed actin filaments, which are enriched at focal adhesions, and to regulate various cellular signalling pathways by shuttling between the cytoplasm and the nucleus. Mainly, the stress sensitivity of the selected LIM proteins is demonstrated in contractile stress fibres and focal adhesion in fibroblasts, with the presence of at least three LIM domains required for force-induced interaction with stressed actin filaments. However, recent studies have expanded our understanding by identifying the LIM-only class of these proteins (LMOs), which contain only two LIM domains, at keratin intermediate filaments in epithelial cells, indicating their importance as signalling hubs in mechanotransduction pathways. In addition, members of the CRP class of LIM domain proteins with only two LIM domains linked to a short glycine-rich repeat can directly bind F-actin even in the absence of mechanical load and can also recruit to the stress fibres in response to stretch. Their dysregulation is linked with several pathological conditions, like cancer metastasis, cardiovascular disorders, muscle disorders, and inflammatory disorders, emphasising their importance in disease progression. This review highlights the diverse roles of LIM-only proteins, LMOs & CRPs in mechanotransduction, emphasising their emerging significance in integrating cytoskeleton dynamics with gene expression and the therapeutic potential of targeting LIM-only proteins to modulate the mechanotransduction pathway in a clinical context.