This has hampered identification of any potential unique signaling roles for PI(3,4)P 2. However, many proteins with modular domains that directly bind to PIP 3, including Akt, also bind to PI(3,4)P 2. PI(3,4)P 2–binding proteins, such as TAPP1/2 and lamellipodin, link PI3K/PI(3,4)P 2 to cytoskeletal remodeling. Class II PI3-kinases also can generate PI(3,4)P 2 by phosphorylating PI4P. SHIP1/2 lipid phosphatases dephosphorylate PIP 3 to generate PI(3,4)P 2, which is degraded further by INPP4A/B to PI3P. In phosphoinositide metabolism, PIP 3, labeled PI(3,4,5)P 3, is generated by phosphorylation of the precursor PI(4,5)P 2 by the action of class I PI3-kinases, and the reverse reaction is generated by the phosphatase PTEN. And PI(3,4)P 2 can be degraded by lipid phosphatases such as PTEN and INPP4B - tumor suppressors frequently inactivated in human cancers. Alternatively, class II PI3-kinases can use PI4P as a substrate to generate PI(3,4)P 2. 5' phosphoinositide phosphatases can dephosphorylate PIP 3 to generate PI(3,4)P 2. Unlike PIP 3, PI(3,4)P 2 can be generated by more than one route of synthesis. Recent studies point to an important role for this neglected lipid second messenger, with some surprises. PIP 3 is a true lipid-derived second messenger: It is absent in unstimulated cells, it is synthesized rapidly at sites of PI3K activation at the plasma membrane, it is removed by the action of the lipid phosphatase and tumor suppressor PTEN, and it initiates PI3K signal relay by recruiting effector proteins such as the serine/threonine protein kinase Akt and downstream nodes such as the mTOR pathway.īy contrast, a separate lipid product of PI3K, PI(3,4)P 2, remained largely out of the limelight. Much of this work focused on the lipid product of PI3K activity, PIP 3, or PI(3,4,5)P 3, derived from the phosphorylation of the membrane phosphoinositide PI(4,5)P 2. The pathway is dysregulated in pathophysiologies such as cancer and diabetes. The phosphoinositide 3-kinase, or PI3K, signaling pathway has been studied intensively since its discovery in the mid-1980s and has been found to play a critical role in the regulation of normal cellular physiology.

Pip3 pathway