(248f) A Diffusion-Reaction Model for Integrin Clustering in Response to Cell Adhesion

Integrins are plasma membrane proteins that anchor cells to the extra-cellular environment, and relay information about the environment back into the cell. A variety of integrin-dependent pathologies have been identified, including cancer, blood clotting disorders, developmental disorders, heart attack, and stroke [1]. Research has elucidated the form and function of many integrin proteins [2], however there is still a deficiency in our understanding of the collective behavior of integrins [3]. Integrins form clusters that anchor cells to the extra-cellular matrix (ECM) and provide a platform for signal transduction and cytoskeletal attachment inside cells [4]. The formation of these clusters is a dynamic, spatially heterogeneous process that alters cell growth and movement through various signaling events. Cells are able to control the size, molecular composition, and temporal characteristics of integrin clusters from within by adjusting integrin functional properties [5]. Our understanding of integrin signaling has been limited by our inability to capture the temporal and spatial complexity that underlies integrin clustering and subsequent signaling events. We have developed a mathematical model of integrin movement and protein clustering that is able to capture different patterns of integrin clustering, depending on values chosen for certain model parameters. By varying model parameters to reflect integrin behavior in response to known stimuli, we are then able to relate collective clustering behavior to specific integrin characteristics.

The model is formulated by assuming that integrins are mobile and subject to Fickian diffusion in the free, unbound state, and that they are immobile when bound to an insoluble ECM substrate. In this model, integrin clusters form via two sequential reactions. An initial, reversible reaction creates a loosely-bound form that quickly converts to a tightly-bound form when stochastic and concentration-dependent requirements are satisfied. Integrin clusters are formed by the association of tightly bound integrins into regions of high concentration. Through the use of this simple framework, we are able to model changes in integrin cluster number, size and formation time. Since integrin clusters form the platform upon which numerous molecules bind and interact, this model creates the framework for a variety of cell signaling models, such as those for migration and anti-apoptosis signals. The coupling of this model to various integrin signaling processes will help us to understand how changes in integrin behavior can lead to various integrin-dependent signaling events.

References

[1] Wehrele-Haller B, and Imhof BA, Journal of Pathology 200, 481-487, 2003

[2] Calderwood DA, J Cell Sci 117 (5), 657-666, 2004

[3] Carman CV, and Springer TA, Curr Opin Cell Biol, 15, 547-556, 2003

[4] Clark EA, and Brugge JS, Science 268, 233-239, 1995

[5] Kim M, Carman CV, Yang W, Salas A, and Springer TA, J Cell Biol 167 (6), 1241-1253, 2004