The protein phosphatase 2A (PP2A) family of heterotrimeric serine-threonine phosphatases participates in human cell transformation. Each functional PP2A complex contains one structural A subunit (A alpha or A beta), and mutations of both are found to occur at low frequency in human tumors. We have shown that A alpha functions as haploinsufficient tumor suppressor gene by regulating in part phosphatidylinositol 3-kinase (PI3K) signaling. In contrast, loss of A beta function due to biallelic alterations contributes to cancer progression through dysregulation of small GTPase RaIA activity. These observations provide evidence that dysfunction of particular PP2A complexes regulate specific phosphorylation event necessary for cancer initiation.