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Force is a signal that cells cannot ignore.

Yusko EC, Asbury CL - Mol. Biol. Cell (2014)

Bottom Line: Cells sense biochemical, electrical, and mechanical cues in their environment that affect their differentiation and behavior.The molecular details underlying how cells respond to force are only beginning to be understood.Here we review tools for probing force-sensitive proteins and highlight several examples in which forces are transmitted, routed, and sensed by proteins in cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195-7290.

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Forces in cells are routed, transmitted, and transduced by mechanically sensitive proteins and have cell-wide implications, influencing biochemical signaling in the cytoplasm and gene expression in the nucleus. Forces generated in the actin cytoskeleton by myosin II cross-bridges are transmitted several micrometers between adhesion proteins in cell membrane and LINC complexes in the nuclear cortex. Tension-dependent unfolding of talin (step 1) reveals substrates for vinculin binding (step 2), which in turn recruits additional actin filaments (steps 3 and 4) as part of focal adhesion development (del Rio et al., 2009; Ciobanasu et al., 2014; Yao et al., 2014). Tension-dependent unfolding of p130Cas reveals phosphorylation sites for Src kinase as part of integrin signaling and ultimately generates the active form of a diffusible GTPase Rap1(steps 5 and 6; Sawada et al., 2006). Concomitantly, tension in the actin cytoskeleton is transmitted through LINC complexes to the nuclear cortex. Lamin A, an intermediate filament of the nuclear cortex, mechanically couples the nuclear cortex to LINC complexes and therefore the cytoplasmic cytoskeleton; it affects DNA transcription of the gene for lamin A and the transcription of stress fiber genes (Swift et al., 2013). Increased cytoskeletal tension on LINC complexes correlates with decreasing phosphorylation of lamin A, decreasing turnover of lamin A in the nuclear cortex, increasing stiffness of the nuclear cortex, and ultimately, through the retnonic acid pathway, increasinglevels of lamin A. Note that many intermediate proteins are not shown, for simplicity.
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Figure 2: Forces in cells are routed, transmitted, and transduced by mechanically sensitive proteins and have cell-wide implications, influencing biochemical signaling in the cytoplasm and gene expression in the nucleus. Forces generated in the actin cytoskeleton by myosin II cross-bridges are transmitted several micrometers between adhesion proteins in cell membrane and LINC complexes in the nuclear cortex. Tension-dependent unfolding of talin (step 1) reveals substrates for vinculin binding (step 2), which in turn recruits additional actin filaments (steps 3 and 4) as part of focal adhesion development (del Rio et al., 2009; Ciobanasu et al., 2014; Yao et al., 2014). Tension-dependent unfolding of p130Cas reveals phosphorylation sites for Src kinase as part of integrin signaling and ultimately generates the active form of a diffusible GTPase Rap1(steps 5 and 6; Sawada et al., 2006). Concomitantly, tension in the actin cytoskeleton is transmitted through LINC complexes to the nuclear cortex. Lamin A, an intermediate filament of the nuclear cortex, mechanically couples the nuclear cortex to LINC complexes and therefore the cytoplasmic cytoskeleton; it affects DNA transcription of the gene for lamin A and the transcription of stress fiber genes (Swift et al., 2013). Increased cytoskeletal tension on LINC complexes correlates with decreasing phosphorylation of lamin A, decreasing turnover of lamin A in the nuclear cortex, increasing stiffness of the nuclear cortex, and ultimately, through the retnonic acid pathway, increasinglevels of lamin A. Note that many intermediate proteins are not shown, for simplicity.

Mentions: Clusters of cell-adhesion proteins occur at focal adhesions and contain multiple mechanosensitive proteins involved in coupling transmembrane α/β-integrins to the actin network. The extracellular portion of α/β-integrins connects to fibronectin in the extracellular matrix (ECM) and exhibits classic catch-bond behavior, likely through an allosteric pathway (Kong et al., 2009). Contractile forces generated in the actomyosin network are transmitted through talin to the integrins and the ECM. Talin contains a C-terminal rod-like structure consisting of 13 α-helical bundles. Under ∼5 pN of tension, several α-helical bundles unfold, revealing binding sites for vinculin (Figure 2; del Rio et al., 2009; Yao et al., 2014). Vinculin binds to these cryptic sites with high affinity (nanomolar range), preventing the α-helical bundles from refolding and recruiting additional actin filaments (Ciobanasu et al., 2014; Yao et al., 2014). The onset of vinculin binding to talin correlates with an increase in the strength of the focal adhesion (Ciobanasu et al., 2014). An intracellular FRET sensor (Figure 1D) inserted into vinculin indicated that each vinculin in a stable focal adhesion supports an average of 2.5 pN, that recruitment of vinculin and force transmission are independently controlled processes, and that the ability of vinculin to transmit force determines whether a focal adhesion will assemble or disassemble under tension (Grashoff et al., 2010).


Force is a signal that cells cannot ignore.

Yusko EC, Asbury CL - Mol. Biol. Cell (2014)

Forces in cells are routed, transmitted, and transduced by mechanically sensitive proteins and have cell-wide implications, influencing biochemical signaling in the cytoplasm and gene expression in the nucleus. Forces generated in the actin cytoskeleton by myosin II cross-bridges are transmitted several micrometers between adhesion proteins in cell membrane and LINC complexes in the nuclear cortex. Tension-dependent unfolding of talin (step 1) reveals substrates for vinculin binding (step 2), which in turn recruits additional actin filaments (steps 3 and 4) as part of focal adhesion development (del Rio et al., 2009; Ciobanasu et al., 2014; Yao et al., 2014). Tension-dependent unfolding of p130Cas reveals phosphorylation sites for Src kinase as part of integrin signaling and ultimately generates the active form of a diffusible GTPase Rap1(steps 5 and 6; Sawada et al., 2006). Concomitantly, tension in the actin cytoskeleton is transmitted through LINC complexes to the nuclear cortex. Lamin A, an intermediate filament of the nuclear cortex, mechanically couples the nuclear cortex to LINC complexes and therefore the cytoplasmic cytoskeleton; it affects DNA transcription of the gene for lamin A and the transcription of stress fiber genes (Swift et al., 2013). Increased cytoskeletal tension on LINC complexes correlates with decreasing phosphorylation of lamin A, decreasing turnover of lamin A in the nuclear cortex, increasing stiffness of the nuclear cortex, and ultimately, through the retnonic acid pathway, increasinglevels of lamin A. Note that many intermediate proteins are not shown, for simplicity.
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Related In: Results  -  Collection

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Figure 2: Forces in cells are routed, transmitted, and transduced by mechanically sensitive proteins and have cell-wide implications, influencing biochemical signaling in the cytoplasm and gene expression in the nucleus. Forces generated in the actin cytoskeleton by myosin II cross-bridges are transmitted several micrometers between adhesion proteins in cell membrane and LINC complexes in the nuclear cortex. Tension-dependent unfolding of talin (step 1) reveals substrates for vinculin binding (step 2), which in turn recruits additional actin filaments (steps 3 and 4) as part of focal adhesion development (del Rio et al., 2009; Ciobanasu et al., 2014; Yao et al., 2014). Tension-dependent unfolding of p130Cas reveals phosphorylation sites for Src kinase as part of integrin signaling and ultimately generates the active form of a diffusible GTPase Rap1(steps 5 and 6; Sawada et al., 2006). Concomitantly, tension in the actin cytoskeleton is transmitted through LINC complexes to the nuclear cortex. Lamin A, an intermediate filament of the nuclear cortex, mechanically couples the nuclear cortex to LINC complexes and therefore the cytoplasmic cytoskeleton; it affects DNA transcription of the gene for lamin A and the transcription of stress fiber genes (Swift et al., 2013). Increased cytoskeletal tension on LINC complexes correlates with decreasing phosphorylation of lamin A, decreasing turnover of lamin A in the nuclear cortex, increasing stiffness of the nuclear cortex, and ultimately, through the retnonic acid pathway, increasinglevels of lamin A. Note that many intermediate proteins are not shown, for simplicity.
Mentions: Clusters of cell-adhesion proteins occur at focal adhesions and contain multiple mechanosensitive proteins involved in coupling transmembrane α/β-integrins to the actin network. The extracellular portion of α/β-integrins connects to fibronectin in the extracellular matrix (ECM) and exhibits classic catch-bond behavior, likely through an allosteric pathway (Kong et al., 2009). Contractile forces generated in the actomyosin network are transmitted through talin to the integrins and the ECM. Talin contains a C-terminal rod-like structure consisting of 13 α-helical bundles. Under ∼5 pN of tension, several α-helical bundles unfold, revealing binding sites for vinculin (Figure 2; del Rio et al., 2009; Yao et al., 2014). Vinculin binds to these cryptic sites with high affinity (nanomolar range), preventing the α-helical bundles from refolding and recruiting additional actin filaments (Ciobanasu et al., 2014; Yao et al., 2014). The onset of vinculin binding to talin correlates with an increase in the strength of the focal adhesion (Ciobanasu et al., 2014). An intracellular FRET sensor (Figure 1D) inserted into vinculin indicated that each vinculin in a stable focal adhesion supports an average of 2.5 pN, that recruitment of vinculin and force transmission are independently controlled processes, and that the ability of vinculin to transmit force determines whether a focal adhesion will assemble or disassemble under tension (Grashoff et al., 2010).

Bottom Line: Cells sense biochemical, electrical, and mechanical cues in their environment that affect their differentiation and behavior.The molecular details underlying how cells respond to force are only beginning to be understood.Here we review tools for probing force-sensitive proteins and highlight several examples in which forces are transmitted, routed, and sensed by proteins in cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195-7290.

Show MeSH
Related in: MedlinePlus