Pdk1^-/- EBs (right) do not develop into networks of ECs.

The phosphatidylinositol 3-kinase (PI3K) signalling pathway and its downstream effectors phosphoinositide-dependent kinase-1 (PDK1) and AKT/PKB are known to regulate cell motility. But the way in which these components interact has yet to be elucidated. It is thought that phosphatidylinositol 3,4,5-trisphosphate (PIP3), the product of PI3K, might be involved in the PDK1-AKT/PKB interaction as both kinases contain a PH domain that binds to PIP3. Now, in the Journal of Cell Biology, Primo et al. report for the first time that PDK1 regulates cell motility by activating AKT/PKB through its interaction with PIP3.

Pdk1^-/- mice lack normal vascularisation, indicating that PDK1 might be required for endothelial cell (EC) migration during vessel formation. The authors found that Pdk1^-/- embryoid bodies (EBs) did not develop into networks of ECs. Pdk1^-/- EC migration was defective and disruption of the PDK1 PH domain led to impaired migration and vessel formation. These observations confirm that PDK1 activity is required for cell migration in ECs.

Overexpression of PDK1 in ECs resulted in an increase in migration that followed the gradient of vascular endothelial growth factor (VEGF). Enhanced migration was associated with increased phosphorylation of AKT/PKB, but not of PDK1, suggesting that AKT/PKB might be responsible for the enhanced migration. Kinase-deficient PDK1 did not induce migration of ECs, indicating that PDK1 is responsible for AKT/PKB phosphorylation. Upon inhibition of PI3K, VEGF-mediated EC migration was reduced. This observation points to a link between PI3K action, VEGF receptor signalling and PDK1 activity.

The authors postulated that PDK1 might activate AKT/PKB via docking to membrane-bound PIP3. This hypothesis was corroborated by the discovery that, in contrast to control PDK1, PDK1 which lacked the PH domain did not relocate to the leading edge. In addition, phosphorylation of AKT/PKB increased at the edge and AKT/PKB colocalised with PDK1 at the plasma membrane.

Based on their results, Primo et al. propose that after exposure to a stimulus such as VEGF, PIP3 synthesis leads to the translocation of PDK1 and AKT/PKB to the EC cell membrane. PDK1 then activates AKT/PKB, which then guides directional cell movement akin to the chemotactic cell motility observed in Dictyostelium discoideum. The results of Primo et al. offer the first evidence that the PI3K signalling pathway is involved in tyrosine kinase receptor-mediated cell migration.

Author: Mirko von Elstermann