Vinculin phosphorylation differentially regulates mechanotransduction at cell–cell and cell–matrix adhesions

117

145

The Abelson tyrosine kinases were initially identified as drivers of leukemia in mice and humans. The Abl family kinases Abl1 and Abl2 regulate diverse cellular processes during development and normal homeostasis, and their functions are subverted during inflammation, cancer and other pathologies. Abl kinases can be activated by multiple stimuli leading to cytoskeletal reorganization required for cell morphogenesis, motility, adhesion and polarity. Depending on the cellular context, Abl kinases regulate cell survival and proliferation. Emerging data support important roles for Abl kinases in pathologies linked to inflammation. Among these are neurodegenerative diseases and inflammatory pathologies. Unexpectedly, Abl kinases have also been identified as important players in mammalian host cells during microbial pathogenesis. Thus, the use of Abl kinase inhibitors might prove to be effective in the treatment of pathologies beyond leukemia and solid tumors. In this Cell Science at a Glance article and in the accompanying poster, we highlight the emerging roles of Abl kinases in the regulation of cellular processes in normal cells and diverse pathologies ranging from cancer to microbial pathogenesis.

Section: Structure Modular Domains and Enzymatic Regulation Of The Amentioning

confidence: 99%

Section: Structure Modular Domains and Enzymatic Regulation Of The Amentioning

confidence: 99%

Multifunctional Abl kinases in health and disease

Khatri

Wang

Pendergast

2016

117

145

“…DeMali and colleagues have demonstrated that applied force on E-cadherin increases the Abl-mediated phosphorylation of vinculin on tyrosine 822 (Y822) and allows vinculin to integrate into E-cadherin-based intercellular junctions (Bays et al, 2014). The degree of Y822-phosphorylated vinculin within adherens junctions then determines the extent to which cadherins transduce force.…”

Section: Introductionmentioning

confidence: 99%

The mechanical regulation of integrin–cadherin crosstalk organizes cells, signaling and forces

Mui

Chen

Assoian

2016

270

224

Cadherins and integrins are intrinsically linked through the actin cytoskeleton and share common signaling molecules. Although mechanosensing by the integrin-actin axis has long been appreciated, a growing body of literature now demonstrates that cadherins also transduce and respond to mechanical forces. Mounting evidence shows that mechanically driven crosstalk between integrins and cadherins regulates the spatial distribution of these receptors, their signaling intermediates, the actin cytoskeleton and intracellular forces. This interplay between integrins and cadherins can control fibronectin matrix assembly and signaling, and a fine balance between traction forces at focal adhesions and intercellular tension at adherens junctions is crucial for directional collective cell migration. In this Commentary, we discuss two central ideas: (1) how the dynamic interplay between integrins and cadherins regulates the spatial organization of intracellular signals and the extracellular matrix, and (2) the emerging consensus that intracellular force is a central mechanism that dictates cell behavior, guides tissue development and ultimately drives physiology.

“…Phosphorylation at position 822 by the kinase Abl is only required for E-cadherin-mediated force transmission and signaling in cell-cell contacts (Subauste et al, 2004), but not for force transmission through cell-ECM adhesions (Bays et al, 2014). By contrast, phosphorylation of vinculin at position 100 and 1065 by Src kinase affects cell spreading and wound repair (Zhang et al, 2004;Moese et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Vinculin phosphorylation at residues Y100 and Y1065 is required for cellular force transmission

Auernheimer

Lautscham

Leidenberger

et al. 2015

The focal adhesion protein vinculin connects the actin cytoskeleton, through talin and integrins, with the extracellular matrix. Vinculin consists of a globular head and tail domain, which undergo conformational changes from a closed auto-inhibited conformation in the cytoplasm to an open conformation in focal adhesions. Srcmediated phosphorylation has been suggested to regulate this conformational switch. To explore the role of phosphorylation in vinculin activation, we used knock-out mouse embryonic fibroblasts re-expressing different vinculin mutants in traction microscopy, magnetic tweezer microrheology, FRAP and actin-binding assays. Compared to cells expressing wild-type or constitutively active vinculin, we found reduced tractions, cytoskeletal stiffness, adhesion strength, and increased vinculin dynamics in cells expressing constitutively inactive vinculin or vinculin where Src-mediated phosphorylation was blocked by replacing tyrosine at position 100 and/or 1065 with a non-phosphorylatable phenylalanine residue. Replacing tyrosine residues with phospho-mimicking glutamic acid residues restored cellular tractions, stiffness and adhesion strength, as well as vinculin dynamics, and facilitated vinculin-actin binding. These data demonstrate that Src-mediated phosphorylation is necessary for vinculin activation, and that phosphorylation controls cytoskeletal mechanics by regulating force transmission between the actin cytoskeleton and focal adhesion proteins.