Signaling Networks in Chemotaxis and Cytokinesis

The mechanisms of sensing shallow gradients of extracellular signals is remarkably similar in Dictyostelium amoebae and mammalian leukocytes. An extensive series of studies have indicated that the upstream components and reactions in the signaling pathway are quite uniform while downstream responses such as PIP3 accumulation and actin polymerization are sharply localized towards the high side of the gradient. We have recently shown that activation of TorC2 and PKB occurs at the leading edge of chemotaxing cells and plays a critical role in directed cell migration. Within seconds of stimulation of chemotactically sensitive cells, two PKB homologs, PKBA and PKBR1, transiently phosphorylate at least 10 proteins. The enzymes are activated by phosphorylation of their hydrophobic motifs (HMs) through TorC2. Cells deficient in both PKBs or TorC2 lack most of the phosphorylated substrates and are specifically impaired in directional sensing. Activation of PKBA requires PIP3 while activation of PKBR1 is independent of PIP 3 . This redundant circuit explains previous observations on the role of PIP 3 in chemotaxis. In cells lacking PTEN, high levels of PIP3 overactivate PKBA and impair chemotaxis by triggering many extraneous pseudopodia. In the absence of PIP3, chemotaxis can occur almost normally because PKBR1 is activated by TorC2 independently of PIP3.