Phosphatases: The New Brakes for Cancer Development?

Figure 1

The primary phosphatases function as tumor suppressors and their signaling pathways. This model demonstrates the roles of PTEN, INPP4B, SHIP1/2, and PP2A in regulation of signaling downstream of PI3K/Akt. Two major phospholipid pools—PI(3,4,5)P3 and PI(3,4)P2—were generated in response to stimulation of PI3K. PTEN hydrolyzed the 3′-phosphate of PI(3,4,5)P3 to terminate PI3K signaling. SHIP family members hydrolyzed the 5′-phosphate of PI(3,4,5)P3 to generate PI(3,4)P2, which, like PI(3,4,5)P3, can facilitate PDK1-dependent phosphorylation and activation of AKT. INPP4B converted PI(3,4)P2 to PI(3)P. PP2A not only dephosphorylated Akt at T308 and S473 and negatively regulated the PI3K/Akt pathway but also stabilized p53 or CDC25 and the 14-3-3 complex, inactivated the oncoprotein c-Myc, and antagonized the Wnt/β-catenin pathway. Red arrows indicate enhancing tumorigenesis activities, and green arrows indicate inhibition of tumorigenesis.