Intracellular signal transduction networks are responsible for controlling cell behavior in response to external stimuli, which are sensed by specific receptors at the cell membrane. Tyrosine-phosphorylated growth factor receptors actuate signal transduction by providing scaffolds for the recruitment of various adaptor proteins and enzymes. Due to the modular nature of signaling protein interactions, these complexes initiate intracellular signaling pathways, which are linked through parallel interactions in the network. To study the spatiotemporal dynamics of crosstalk between signaling pathways at the early stages of signal transduction, we have developed a Brownian dynamics modeling approach and applied it to the receptor-mediated activation of Ras and the cooperative recruitment of phosphoinositide 3-kinase (PI3K) by activated receptors and Ras. The key ingredients of the model are: 1) the modular nature of domains used by signaling proteins for various catalytic and noncatalytic interactions, and 2) the relatively slow lateral mobility of membrane-anchored molecules over macroscopic length scales, which tends to control the rates of intermolecular binding at the membrane. Various analyses of the model simulations show that cooperative assembly of multi-molecular complexes nucleated by activated receptors is facilitated by the local release and capture of membrane-anchored signaling molecules (such as active Ras) from/by receptor-bound signaling proteins. The model shows that PI3K is most likely to be recruited by activated receptors bound by the enzyme that activates Ras. By this spatial coupling mechanism, receptor-bound PI3K is stabilized through short-range, diffusion-controlled capture of active Ras and Ras/PI3K complexes released from the receptor complex. We contend that this mechanism is a means by which many signaling pathways are propagated and spatially coordinated for efficient crosstalk between them.

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