The study of phosphoinositides (also called inositol phospholipids) in plasma-membrane signaling began in 1953. In the same year the DNA double helix was solved, the Hokins found that treating pigeon pancreas slices with acetylcholine increased the incorporation of radiolabeled phosphate into the lipid fraction. The lipids mainly responsible were phosphoinositides. At the time this was thought to compensate for the loss of phospholipids accompanying the amylase secretory response, but by the 1970s the phenomenon had been observed across many combinations of cells and receptor agonists. In particular, Michell and colleagues proposed a link to intracellular calcium mobilization, and it came to be regarded as a general early cellular response to extracellular signals.
Subsequently, Takai, Nishizuka, and colleagues showed in the late 1970s that diacylglycerol (DAG), produced by breakdown of PI(4,5)P2, is an activator of protein kinase C (PKC), and Berridge and colleagues found in the early 1980s that Ins(1,4,5)P3 triggers calcium release from the endoplasmic reticulum. With the identification of the IP3 receptor by Mikoshiba and colleagues, the significance of the so-called "PI turnover" came to be explained at the molecular level. Through this series of discoveries, PI(4,5)P2 was positioned as the precursor of two second messengers, DAG and Ins(1,4,5)P3, and Nishizuka and Berridge received the Lasker Award in 1989. Around the same time, Lindberg and Takenawa and colleagues found that PI(4,5)P2 binds actin-regulating proteins. Phosphoinositides thus came to be understood not only as molecules broken down to generate second messengers, but also as lipid signaling molecules that directly regulate protein function on membranes.
The link between cancer and phosphoinositides emerged from the discovery of a trace phosphoinositide phosphorylated at the 3-position hydroxyl of the inositol ring and of its producing enzyme, phosphoinositide 3-kinase (PI3K). In the mid-1980s, Sklar, Cantley, and colleagues identified PI3K as an oncogenic protein binding polyoma middle T antigen. This brought a new direction to phosphoinositide research, which had centered on the breakdown of PI(4,5)P2 by phospholipase C and the production of second messengers — namely, the concept that phosphoinositides themselves act as signaling molecules controlling cell proliferation, survival, and transformation.
It later became clear that PI3K phosphorylates PI(4,5)P2 to produce PI(3,4,5)P3, and that PI(3,4,5)P3 recruits proteins bearing a pleckstrin homology (PH) domain to the plasma membrane. In particular, the membrane translocation and activation of Akt/PKB was established as a central molecular mechanism of PI3K signaling. PI3K-mediated PI(3,4,5)P3 production is a major pathway converting extracellular signals such as growth factors and cytokines into intracellular proliferation and survival programs, and was shown to play an important role in how cancer cells acquire proliferative and survival capacities.
Within this stream, Maehama, Dixon, and colleagues revealed that the tumor-suppressor gene product PTEN is a lipid phosphatase that dephosphorylates PI(3,4,5)P3. PTEN removes the 3-position phosphate of PI(3,4,5)P3 to convert it back to PI(4,5)P2 — that is, it catalyzes the reverse reaction of PI3K. Around the same time, knockout-mouse technology was being established, and Suzuki, Mak, and colleagues generated PTEN-deficient mice and found that Akt signaling is constitutively activated. They further demonstrated that PTEN deficiency causes excessive accumulation of PI(3,4,5)P3, making clear that the breakdown of intracellular signaling due to abnormal phosphoinositide metabolism is directly linked to cancer onset. The thin-layer chromatography measurement of PI(3,4,5)P3 in this work was carried out by Sasaki, and became an important starting point for subsequent research.
In the 2000s, as gene sequencing became widespread, amplification of PIK3CA (which encodes PI3Kα) and hotspot mutations increasing its enzymatic activity were found in various cancers, and abnormal phosphoinositide metabolism via PI3K/PTEN became widely recognized as a representative metabolic abnormality in cancer. Moreover, genetic analyses in knockout mice and human disease have shown that abnormalities in the metabolism of phosphoinositides such as PI(3)P, PI(3,4)P2, PI(3,5)P2 are involved not only in cancer but in diverse biological processes and pathologies — inflammation, immune disorders, neuropsychiatric diseases, metabolic disorders, cardiovascular diseases, and developmental abnormalities (figure below). Building on these insights, mechanistic studies at the cellular and molecular levels are now revealing how each phosphoinositide controls cellular function and how its breakdown leads to disease, and development toward medical applications is advancing.