Fig. 3. Spatial-temporal regulation of PTEN and PI3K induces cell polarization in response to a chemoattractant signal. (A) In unstimulated cells, Class I PI3K is mainly cytoplasmic, whereas PTEN is localized at the plasma membrane, resulting in a homogenous distribution of PtdIns(4,5)P₂ in the plasma membrane. (B) When cells sense the chemoattractant signal, a signaling pathway yet to be identified promotes the rapid PI3K translocation to the leading edge facing the higher chemoattractant concentration and the delocalization of PTEN from the leading edge. Therefore, PtdIns(3,4,5)P₃ is synthesized from PtdIns(4,5)P₂ at the leading edge and prevented from accumulating on the sides and at the back of the cell by PTEN, causing a very steep anterior/posterior PtdIns(3,4,5)P₃ gradient. (C) PtdIns(3,4,5)P₃ recruits and activates at the leading edge RhoGEF proteins and other PH domain-containing proteins. The activity of these proteins is important to stimulate the actin polymerization necessary for cell motility. In coordination with these events in the leading edge, signaling by one or more pathways that remain to be identified restricts certain proteins to the back of the cell. These proteins are important for inhibiting pseudopod protrusion from the sides of the cell and for retracting the back of the cell while the leading edge is moving forward.