It is known that platelet derived growth factor (PDGF) induced Rac activation depends on Src activity. However, we find that a local stress of physiologic magnitude via integrins can directly activate Rac GTPase rapidly, independent of the Src activity. Our finding on the stress-induced rapid Rac activation challenges the conventional wisdom on mechanotransduction and suggests that stress-induced signaling via focal adhesions does not follow signal transduction pathways induced by growth factors. To view the whole paper:
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007…
focal complex and focal adhesion
Dear Prof.Wang,
This work is really a good example of "Mechanotransduction at a distance" <Your reivew in NATURE REVIEWS>. During integrin-mediated adhesions such as focal complex and focal adhesion, RAC and RHO pathways are coupled (see Fig.4 in Geiger et al. 2001 Current Opinion in Cell Biology 13 584-592), and RAC and RHO proteins are negative regulators of each other. As I know, RAC is related to focal complex and RHO to focal adhesion. In some sense, RHO can be replaced with external tension to promote focal adhesion growth. Is it meaning that the remote focal adhesions are still stable, and focal complexes are active, under the mechanical perturbation?
I am not sure the answer, but am sure that this is a naïve question:) for that to understand these complex proteins and molecular pathways are so difficult.
In reply to focal complex and focal adhesion by kongdong
focal complex and focal adhesion and threshold strain
Dear Dong,
Thank you for your comments. You are correct that Rac and Rho are negative regulators of each other. Since we do not have a Rho-biosensor to measure its activity simultaneously in the same cell, we do not know if Rho is inhibited by the applied stress (we mentioned this at the end of the paper). But it is possible.
A focal complex is a small, dynamic, nascent aggregation of focal proteins whereas a focal adhesion is a large, more stable subcellular structure that can sustain stresses for longer periods of time and maintain cell shape stability.
We have not examined the size, dynamics, and protein activities at focal complexes or focal adhesions. But my guess is that they might be altered by the applied stress via the bead. This is an excellent question.
I would like to point out that although the applied stress can activate Src (S Na et al, PNAS, 2008) and Rac (this PLoS One paper) at a distance in these differentiated cells (smooth muscle cells, fibroblasts), the stress amplitude is NOT big enough to trigger the active cell spreading process. In sharp contrast, embryonic stem cells (ESCs) spread and differentiate in response to the similar amplitude of stress (F Chowdhury et al, Nature Materials, 2009). The reason is that ESCs intrinsically are ~10 times softer. Together these papers have addressed an important question: do cells respond to stress or to strain? Or stress and strain are equivalent in a living cell?
Our findings suggest that the critical parameter is the threshold strain: only when the induced intracellular strain (=applied stress divided by cell stiffness) is greater than this threshold strain (~1-3%), the cell will elicit a biological response of spreading. Below this value, although Src and Rac are activated, it is not sufficient to trigger a spreading response. This suggests that this threshold strain corresponds to other intracellular strain sensors that need to be deformed enough to be activated to trigger the spreading response. This mechanism is consistent with the published data on the intracellular protein unfolding and/or conformational change by force (see papers by D Discher lab (Science, 07), M Sheetz lab (Science, 09)). Our Nature Materials paper has put their protein opening findings in the context of the biological response of spreading, one of the most important primitive functions of all anchorage-dependent cells.