PTEN and myotubularin: Novel phosphoinositide phosphatases

Protein tyrosine phosphatases (PTPs) are a diverse group of enzymes that co ntain a highly conserved active site motif, Cys-x(5)-Arg (Cx(5)R). The PTP super family enzymes, which include tyrosine-specific, dual specificity, lo w-molecular-weight, and Cdc25 phosphatases, are key mediators of a wide var iety of cellular processes, including growth, metabolism, differentiation, motility, and programmed cell death. The PTEN/MMAC1/TEP1 gene was originall y identified as a candidate tumor suppressor gene located on human chromoso me 10q23; it encodes a protein with sequence similarity to PTPs and tensin. Recent studies have demonstrated that PTEN plays an essential role in regu lating signaling pathways involved in cell growth and apoptosis, and mutati ons in the PTEN gene are now known to cause tumorigenesis in a number of hu man tissues. In addition, germ line mutations in the PTEN gene also play a major role in the development of Cowden and Bannayan-Zonana syndromes, in w hich patients often suffer from increased risk of breast and thyroid cancer s. Biochemical studies of the PTEN phosphatase have revealed a molecular me chanism by which tumorigenesis may be caused in individuals with PTEN mutat ions. Unlike most members of the PTP superfamily, PTEN utilizes the phospho inositide second messenger, phosphatidylinositol 3,4,5-trisphosphate (PIP3) , as its physiologic substrate. This inositol lipid is an important regulat or of cell growth and survival signaling through the Ser/Thr protein kinase s PDK1 and Akt. By specifically dephosphorylating the D3 position of PIP3, the PTEN tumor suppressor functions as a negative regulator of signaling pr ocesses downstream of this lipid second messenger. Mutations that impair PT EN function result in a marked increase in cellular levels of PIP3 and cons titutive activation of Akt survival signaling pathways, leading to inhibiti on of apoptosis, hyperplasia, and tumor formation. Certain structural featu res of PTEN contribute to its specificity for PIP3, as well as its role(s) in regulating cellular proliferation and apoptosis. Recently, myotubularin, a second PTP superfamily enzyme associated with human disease, has also be en shown to utilize a phosphoinositide as its physiologic substrate.