  In many cellular signaling pathways, key components form clusters at the cell
membrane. Although much work has focused on the mechanisms behind such cluster
formation, the implications for downstream signaling remain poorly understood.
Here, motivated by recent experiments, we study via particle-based simulation a
covalent modification network in which the activating component is either
clustered or randomly distributed on the membrane. We find that while
clustering reduces the response of a single-modification network, clustering
can enhance the response of a double-modification network. The reduction is a
bulk effect: a cluster presents a smaller effective target to a substrate
molecule in the bulk. The enhancement, on the other hand, is a local effect: a
cluster promotes the rapid rebinding and second activation of singly active
substrate molecules. As such, the enhancement relies upon frequent collisions
on a short timescale, which leads to a diffusion coefficient at which the
enhancement is optimal. We complement simulation with analytic results at both
the mean-field and first-passage distribution levels. Our results emphasize the
importance of spatially resolved models, showing that significant effects of
spatial correlations persist even in spatially averaged quantities such as
response curves.
