The guidance strategy of a cell varies with the chemotactic gradient: in steep gradients, cells produce pseudopodia directly up the gradient, but in weak gradients, pseudopodia are produced at random, with cells steering by favouring the pseudopod that is furthest up the gradient. Cells can also become polarized such that they maintain the same front end, even when forced to change direction by a changing gradient.Chemotactic gradients cause Dictyostelium amoebae and neutrophils to produce aligned gradients of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) in their plasma membranes. Genetic experiments that ablate the PtdIns(3,4,5)P3 kinases and the PtdIns(3,4,5)P3 phosphatases that are producing these gradients show that gradients are important for basic cell motility and chemotaxis in weak gradients, but are not essential for chemotaxis in strong gradients.Genetic experiments suggest that Dictyostelium chemotactic signalling to cyclic AMP (cAMP) is channelled through redundant Ras proteins that activate phosphatidylinositol 3-kinases and the target of rapamycin complex-2 (TORC2) in parallel and, eventually, cyclic GMP production. Phospholipase A2 is also activated by cAMP and is important for chemotaxis.The leading edge is extended partially by the force of dendritic actin polymerization beneath the membrane, but also, possibly, by the collision of travelling filamentous-actin waves with the membrane.Hydrostatic pressure contributes to the movement of various cell types, providing an alternative force for extending the leading edge. Hydrostatic pressure tends to produce blebs and is dependent on myosin II.Moving cells may have to regulate their surface area as they change shape and, because the plasma membrane is mostly inextensible, this might require an intimate coordination of movement with the endocytic cycle.
