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. 1. Introduction The phosphatidylinositol (PI) 3-kinase (PI3K) signaling pathway is a normal signal transduction cascade that exists in all types of cells and is physiologically involved in cell proliferation, survival, protein synthesis, metabolism, differentiation, and motility. In physiological situations, many growth factors and regulators can stimulate or activate this pathway. The PI3K pathway contains the upstream PI3K, which phosphorylates the D-3 position of PI, PI 4-phosphate, and PI 4,5-bisphosphate (PIP2) to produce PI 3-phosphate, PI 3,4-bisphosphate (PI(3,4)P2), and PI 3,4,5-trisphosphate (PI(3,4,5)P3 or PIP3), respectively [1], as well as Akt and its kinases PDK1, targets at Thr308 of Akt, and PDK2 which targets at Ser473 of Akt [2]. The second messengers of PIs are associated with major cellular functions such as growth, differentiation, apoptosis, protein trafficking, and motility. Several studies have identified inositol polyphosphate phosphatases, including three major PIP2/PIP3-degrading enzymes: (1) phosphatase and tensin homologue deleted on chromosome 10 (PTEN), an ubiquitously expressed tumor suppressor that converts PI(3,4,5)P3 to PI(4,5)P2 by dephosphorylating the 3-position of PI(3,4,5)P3; (2) Src homology 2 (SH2)-containing inositol 5′-phosphatase (SHIP), which dephosphorylates the 5-position PI(4,5)P3 to produce PI(4)P and hydrolyzes PI(3,4,5)P3 to PI(3,4)P2 phosphatase [3]; (3) inositol polyphosphate 4-phosphatase type II (INPP4B), which hydrolyzes the
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