which have shown to have high affinity with the Akt PH domain. Once bound to the PM through its interaction with PtdIns(3,4)P2 and PtdIns(3,4,5)P3, Akt is activated through release of its auto-inhibitory interaction between the PH and kinase domains. Following this release, T308 in the proteins activation loop and S437 in the proteins hydrophobic domain are phosphorylated by Phosphoinositide-dependent kinase-1 (PDK1) and mechanistic target of Rapamycin Complex 2 (mTORC2), respectively. Test tube experiments have shown that the essential recruitment of PDK1 for Akt activation at the PM can be driven through interactions with both PtdIns(3,4)P2 and PtdIns(3,4,5)P3. It was originally presumed that 5-phosphatases dephosphorylation of PI(3,4,5)P3 would be anti-tumoral, similar to tumor suppressor PTEN. Yet the 5-phosphatase SHIP proteins synthesis of PI(3,4)P2 has been linked to tumor cell survival due to the lipid’s binding and subsequent activation of Akt. Akt activation causes downstream metabolism alterations, apoptosis suppression and a rise in cell proliferation. This pathway and its effects have shown up in 50% of cancers. In conjunction, investigators have shown a rise in PI(3,4)P2 levels and mutation of 4-phosphatase INPP4B has shown mammary epithelial transformation. Recently, PtdIns(3,4)P2 has been shown to play an important role in vesicle maturation during clathrin-mediated endocytosis (CME) (https://en.wikipedia.org/wiki/Receptor-mediated_endocytosis). PtdIns(4)P synthesizing phosphatases SHIP2 and synaptojanin are recruited to clathrin structures at the beginning of the CME process. This production of PtdIns(4)P subsequently leads to PtdIns(3,4)P2 synthesis through PI3K-C2α11, and the newly synthesized PtdIns(3,4)P2 then recruits SNX9 and SNX18 PX-BAR domain proteins which narrow the nascent vesicles neck to eventually be cut and released by dynamin, forming vesicles. PI(3,4)P2 plays another possible role at the PM, promoting cytoskeletal rearrangements through actin regulatory proteins like Lamellipodin. Lamellipodin is recruited to the PM where it is believed to interact with PI(3,4)P2 through its PH domain. Once at the PM, it can regulate lamellipodia actin networks and cell migration by interacting with actin-binding proteins like Ena/VASP. References Phospholipids