Membrane Recruitment as a Cancer Mechanism: A Case Study of Akt PH Domain

[Reviewed by (–)]. The pathway is triggered by Ras activation of membrane-bound phosphatidylinositol-3-kinase (PI3K) at the surface of the plasma membrane. In turn, PI3K phosphorylates the substrate lipid phosphatidylinositol-4,5-bisphosphate (PIP2), yielding the product signaling lipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). Both Akt/protein kinase B (Akt) and phosphoinositide-dependent kinase 1 (PDK1) possess pleckstrin homology (PH) domains that specifically bind PIP3, thereby recruiting these kinases to the plasma membrane where PDK1 phosphorylates Akt at one or more specific sites required for activation of Akt kinase. Ultimately, the PIP3 signal is degraded by the membrane-bound phosphatase PTEN, yielding PIP2. The E17K mutation in the PIP3 binding pocket of Akt PH domain enhances membrane recruitment (), and leads to higher than native levels of phospho-activated Akt. Both PI3K and PTEN possess C2 domains believed to be involved in the plasma membrane recruitment of these enzymes (, ). Such C2 domains often bind lipids in a Ca2+-dependent or -independent manner and serve as membrane targeting modules (, ). Although the PI3K and PTEN C2 domains have both been reported to dock to phospholipid vesicles (, ), high affinity target lipids have not yet been identified for these domains.

Publication

Membrane Recruitment as a Cancer Mechanism: A Case Study of Akt PH Domain. () Joseph J. Falke. Cellscience. ;4(2):25-30. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

Disease mentions