  Integrins are allosteric cell adhesion receptors that control many important
processes, including cell migration, proliferation, and apoptosis. Ligand
binding activates integrins by stabilizing an integrin conformation with
separated cytoplasmic tails, thus enabling the binding of proteins that mediate
cytoplasmic signaling. Experiments demonstrate a high sensitivity of integrin
signaling to ligand density and this has been accounted mainly to avidity
effects. Based on experimental data we have developed a quantitative Monte
Carlo model for integrin signal initiation. We show that within the
physiological ligand density range avidity effects cannot explain the
sensitivity of cellular signaling to small changes in ligand density. Src
kinases are among the first proteins to be activated, possibly by trans
auto-phosphorylation. We calculate the extent of integrin and ligand clustering
as well as the speed and extent of Src kinase activation by trans
auto-phosphorylation or direct binding at different experimentally monitored
ligand densities. We find that the experimentally observed ligand density
dependency can be reproduced if Src kinases are activated by trans
auto-phosphorylation or some other mechanism limits integrin-dependent Src
kinase activation. We propose that Src kinase and thus cell activation by trans
auto-phosphorylation may provide a mechanism to enable ligand-density dependent
responses at physiological ligand densities. The capacity to detect small
differences in ligand density at a ligand density that is large enough to
permit cell adhesion is likely to be important for haptotaxis.
