Kinetic model for lamellipodal actin-integrin 'clutch' dynamics.
In migrating cells, with especial prominence in lamellipodial protrusions at the cell front, highly dynamic connections are formed between the actin cytoskeleton and the extracellular matrix through linkages of integrin adhesion receptors to actin filaments via complexes of cytosolic "connector" proteins. Myosin-mediated contractile forces strongly influence the dynamic behavior of these adhesion complexes, apparently in two counter-acting ways: negatively as the cell-generated forces enhance complex dissociation, and at the same time positively as force-induced signaling can lead to strengthening of the linkage complexes. The net balance arising from this dynamic interplay is challenging to ascertain a priori, rendering experimental studies difficult to interpret and molecular manipulations of cell and/or environment difficult to predict. We have constructed a kinetics-based model governing the dynamic behavior of this system. We obtained ranges of parameter value sets yielding behavior consistent with that observed experimentally for 3T3 cells and for CHO cells, respectively. Model simulations are able to produce results for the effects of paxillin mutations on the turnover rate of actin/integrin linkages in CHO cells, which are consistent with recent literature reports. Overall, although this current model is quite simple it provides a useful foundation for more detailed models extending upon it.
Macdonald
Alice
A
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Horwitz
A Rick
AR
Lauffenburger
Douglas A
DA
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D005109:Extracellular Matrix / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D009218:Myosins / Q000378:metabolism; D051419:Paxillin / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism*; D013379:Substrate Specificity
D000199:Actins; D016023:Integrins; D051419:Paxillin; D009218:Myosins