Theoretical intracellular phosphorylation gradients. (A and B), a model proposed by Brown and Kholodenko [21, 22] predicted that spatial separation of opposing activities (kinase and phosphatase (Ptase)) could produce a gradient (red to yellow) of activated substrates within the cell. The gradients could originate from the plasma membrane (A), or an intracellular structure such as chromatin (B), with the opposing activity homogenously distributed in the cytoplasm. The slope of the gradient is determined by α = √ kp/D where kp is phosphatase activity and D is the diffusion coefficient for proteins in the cytoplasm. (C), a model demonstrating how changes in cell shape can regulate intracellular gradients as proposed by Meyers and Odde . Flattening of the cell at a protrusion or a trailing edge can cause localized increase in phosphorylation of a diffusible substrate, while an increase in cell thickness will cause dephosphorylation.