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A kinetic model for RNA-interference of focal adhesions

Hoffmann, Max ; Schwarz, Ulrich Sebastian

In: BMC Systems Biology, 7 (2013), Nr. 2. pp. 1-18. ISSN 1752-0509

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Download (7MB) | Lizenz: Creative Commons LizenzvertragA kinetic model for RNA-interference of focal adhesions by Hoffmann, Max ; Schwarz, Ulrich Sebastian underlies the terms of Creative Commons Attribution 3.0 Germany

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Abstract

Background: Focal adhesions are integrin-based cell-matrix contacts that transduce and integrate mechanical and biochemical cues from the environment. They develop from smaller and more numerous focal complexes under the influence of mechanical force and are key elements for many physiological and disease-related processes, including wound healing and metastasis. More than 150 different proteins localize to focal adhesions and have been systematically classified in the adhesome project ( http://www.adhesome.org). First RNAi-screens have been performed for focal adhesions and the effect of knockdown of many of these components on the number, size, shape and location of focal adhesions has been reported. Results: We have developed a kinetic model for RNA interference of focal adhesions which represents some of its main elements: a spatially layered structure, signaling through the small GTPases Rac and Rho, and maturation from focal complexes to focal adhesions under force. The response to force is described by two complementary scenarios corresponding to slip and catch bond behavior, respectively. Using estimated and literature values for the model parameters, three time scales of the dynamics of RNAi-influenced focal adhesions are identified: a sub-minute time scale for the assembly of focal complexes, a sub-hour time scale for the maturation to focal adhesions, and a time scale of days that controls the siRNA-mediated knockdown. Our model shows bistability between states dominated by focal complexes and focal adhesions, respectively. Catch bonding strongly extends the range of stability of the state dominated by focal adhesions. A sensitivity analysis predicts that knockdown of focal adhesion components is more efficient for focal adhesions with slip bonds or if the system is in a state dominated by focal complexes. Knockdown of Rho leads to an increase of focal complexes. Conclusions: The suggested model provides a kinetic description of the effect of RNA-interference of focal adhesions. Its predictions are in good agreement with known experimental results and can now guide the design of RNAi-experiments. In the future, it can be extended to include more components of the adhesome. It also could be extended by spatial aspects, for example by the differential activation of the Rac- and Rho-pathways in different parts of the cell.

Item Type: Article
Journal or Publication Title: BMC Systems Biology
Volume: 7
Number: 2
Publisher: BioMed Central
Place of Publication: London
Date Deposited: 22 Feb 2016 13:31
Date: 2013
ISSN: 1752-0509
Page Range: pp. 1-18
Faculties / Institutes: The Faculty of Physics and Astronomy > Institute for Theoretical Physics
Service facilities > Bioquant
Subjects: 570 Life sciences
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