PTEN in brain tumors.The tumor suppressor PTEN dephosphorylates phospholipids generated through the activity of PI3K. PTEN thus antagonizes PI3K activity and regulates a multitude of cellular processes such as angiogenesis, motility, invasiveness, survival and proliferation, all of which can initiate and sustain the malignant phenotype. Although PTEN's lipid phosphatase activity is key to its tumor suppressive functions, it also dephosphorylates protein substrates and interacts with other key regulatory molecules, salient among them the tumor suppressor p53. Given the critical roles of PTEN in cellular homeostasis, it is not surprising that both PTEN expression levels and PTEN protein activities are tightly controlled by a complex conglomeration of molecules that regulate post-translational modifications, subcellular localization, transcriptional activation and transcriptional repression. As one of the most commonly altered molecules in human disease, PTEN plays an important role in a myriad of signaling cascades, and plays a central role in normal brain development and brain tumor pathogenesis. As such it influences prognosis of human cancer, predicts response to therapy, constitutes the lynchpin of genetic syndromes, and may underlie neurocognitive abnormalities such as autism spectrum disorders and Alzheimer's disease. Thus, targeting PTEN and its signaling affiliates sows the seeds for combating not only cancer but also neurocognitive disorders.