Affiliations: Department of Biochemistry, University of Oxford,
South Parks Road, Oxford, OX1 3QU, UK | Biophysics & Bionics Lab, Department of Physics,
Kazan State University, Kazan, 420008, Russian Federation | Kazan Institute of Biochemistry and Biophysics,
Russian Academy of Sciences, Kazan, 420011, Russian Federation
Abstract: Cell migration has long been studied by a variety of techniques and
many proteins have been implicated in its regulation. Integrins, key proteins
that link the cell to the extracellular matrix, are central to adhesion
complexes whose turnover defines the rate of cell locomotion. The formation and
disassembly of these adhesions is regulated by both intracellular and
extracellular factors. In this study we have focused on the
Ca^{2+}-dependent protein network (module) that disassembles
the adhesion complexes. We have developed a mathematical model that includes
the Ca^{2+}-dependent enzymes μ-calpain and phospholipase
C (PLC) as well as IP_{3} receptors and stretch activated
Ca^{2+} channels, all of which have been reported to
regulate migration. The model also considers the spatial effects of
Ca^{2+} propagation into lamella. Our model predicts
differential activation of calpain at the leading and trailing edges of the
cell. Since disassembly of integrin adhesive contacts is proportional to the
degree of calpain activation, this leads to cell migration in a preferred
direction. We show how the dynamics of Ca^{2+} spiking
affects calpain activation and thus changes the disassembly rate of adhesions.
The spiking is controlled by PLC activity and currents through
stretch-activated Ca^{2+} channels. Our model thus combines
the effects of various molecular factors and leads to a consistent explanation
of the regulation of the rate and direction of cell migration.
