Crosstalk between Cell Adhesion Complexes in Regulation of Mechanotransduction

Abstract

Physical forces regulate numerous biological processes during development, physiology, and pathology. Forces between the external environment and intracellular actin cytoskeleton are primarily transmitted through integrin-containing focal adhesions and cadherin-containing adherens junctions. Crosstalk between these complexes is well established and modulates the mechanical landscape of the cell. However, integrins and cadherins constitute large families of adhesion receptors and form multiple complexes by interacting with different ligands, adaptor proteins, and cytoskeletal filaments. Recent findings indicate that integrin-containing hemidesmosomes oppose force transduction and traction force generation by focal adhesions. The cytolinker plectin mediates this crosstalk by coupling intermediate filaments to the actin cytoskeleton. Similarly, cadherins in desmosomes might modulate force generation by adherens junctions. Moreover, mechanotransduction can be influenced by podosomes, clathrin lattices, and tetraspanin-enriched microdomains. This review discusses mechanotransduction by multiple integrin-and cadherin-based cell adhesion complexes, which together with the associated cytoskeleton form an integrated network that allows cells to sense, process, and respond to their physical environment.

Hemidesmosome-Related Keratin Filament Bundling and Nucleation

“…The keratin cytoskeleton is a hallmark feature of epithelial cells [1,2]. It consists of a filamentous cytoplasmic network with unique biomechanical properties that is connected to desmosomes at cell-cell adhesion sites and to hemidesmosomes at epithelial-extracellular matrix (ECM) interfaces [3][4][5][6]. Its 3D organization and dynamic features rely on the other two major cytoskeletal filament systems, i.e., the actin-based microfilaments, which are anchored to adherens junctions at cell-cell borders and to focal adhesions at cell-ECM contacts, and the tubulin-based microtubules [7][8][9][10][11].…”

“…Basal epidermal cells contain keratins 5 and 14, which have been shown to bind to the hemidesmosomal plakin family cytolinkers plectin 1a [15] and bullous pemphigoid antigen 1 (BPAG-1; also referred to as BPAG-1e or BP230) [16]. These linker molecules, in turn, facilitate the attachment to the hemidesmosome-specific α6β4integrin heterodimers [6,17], which bind to laminin 332 in the basement membrane [18,19]. Type II hemidesmosomes of simple epithelia consist only of α6β4-integrin heterodimers and plectin 1a-attached keratins, whereas type I hemidesmosomes, which occur in basal cells of pseudostratified and stratified epithelia, contain additional proteins, such as BPAG-1, the tetraspanin CD151, and the laminin 332-binding BPAG-2 (also referred to as BP180 or collagen type XVII) [6,20].…”

“…These linker molecules, in turn, facilitate the attachment to the hemidesmosome-specific α6β4integrin heterodimers [6,17], which bind to laminin 332 in the basement membrane [18,19]. Type II hemidesmosomes of simple epithelia consist only of α6β4-integrin heterodimers and plectin 1a-attached keratins, whereas type I hemidesmosomes, which occur in basal cells of pseudostratified and stratified epithelia, contain additional proteins, such as BPAG-1, the tetraspanin CD151, and the laminin 332-binding BPAG-2 (also referred to as BP180 or collagen type XVII) [6,20]. Recent studies suggest that type II hemidesmosomes mature into type I hemidesmosomes [21].…”

Integrin Regulation in Immunological and Cancerous Cells and Exosomes

“…Integrin–ligand engagement induces the accumulation of numerous proteins at the integrin CT to form focal adhesions at cell–cell or cell–ECM junctions. The most prominent proteins involved are talin and vinculin, which directly link the integrin to actomyosin [ 41 ]. Notably, force transmission on talin is dependent on actin flow.…”

“…The piconewton forces applied via integrins are finally transmitted to cytoskeletal actin, culminating in alterations of cytoplasmic protein synthesis, signaling pathways and cellular functions, such as tissue morphogenesis, migration, proliferation and differentiation. Dysregulation in integrin-ECM bidirectional mechano-transmission can give rise to many pathologic conditions, including cancer [ 41 ].…”