Phosphatases: the new brakes for cancer development?

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway plays a pivotal role in the maintenance of processes such as cell growth, proliferation, survival, and metabolism in all cells and tissues. Dysregulation of the PI3K/Akt signaling pathway occurs in patients with many cancers and other disorders. This aberrant activation of PI3K/Akt pathway is primarily caused by loss of function of all negative controllers known as inositol polyphosphate phosphatases and phosphoprotein phosphatases. Recent studies provided evidence of distinct functions of the four main phosphatases-phosphatase and tensin homologue deleted on chromosome 10 (PTEN), Src homology 2-containing inositol 5'-phosphatase (SHIP), inositol polyphosphate 4-phosphatase type II (INPP4B), and protein phosphatase 2A (PP2A)-in different tissues with respect to regulation of cancer development. We will review the structures and functions of PTEN, SHIP, INPP4B, and PP2A phosphatases in suppressing cancer progression and their deregulation in cancer and highlight recent advances in our understanding of the PI3K/Akt signaling axis.

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.