PTEN and Myotubularin: Novel Phosphoinositide Phosphatases

Abstract

Protein tyrosine phosphatases (PTPs) are a diverse group of enzymes that contain a highly conserved active site motif, Cys-x5-Arg (Cx5R). The PTP superfamily enzymes, which include tyrosine-specific, dual specificity, low-molecular-weight, and Cdc25 phosphatases, are key mediators of a wide variety of cellular processes, including growth, metabolism, differentiation, motility, and programmed cell death. The PTEN/MMAC1/TEP1 gene was originally identified as a candidate tumor suppressor gene located on human chromosome 10q23; it encodes a protein with sequence similarity to PTPs and tensin. Recent studies have demonstrated that PTEN plays an essential role in regulating signaling pathways involved in cell growth and apoptosis, and mutations in the PTEN gene are now known to cause tumorigenesis in a number of human 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 which patients often suffer from increased risk of breast and thyroid cancers. Biochemical studies of the PTEN phosphatase have revealed a molecular mechanism by which tumorigenesis may be caused in individuals with PTEN mutations. Unlike most members of the PTP superfamily, PTEN utilizes the phosphoinositide second messenger, phosphatidylinositol 3,4,5-trisphosphate (PIP3), as its physiologic substrate. This inositol lipid is an important regulator of cell growth and survival signaling through the Ser/Thr protein kinases PDK1 and Akt. By specifically dephosphorylating the D3 position of PIP3, the PTEN tumor suppressor functions as a negative regulator of signaling processes downstream of this lipid second messenger. Mutations that impair PTEN function result in a marked increase in cellular levels of PIP3 and constitutive activation of Akt survival signaling pathways, leading to inhibition of apoptosis, hyperplasia, and tumor formation. Certain structural features 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 been shown to utilize a phosphoinositide as its physiologic substrate.

Tumours and tremors: how PTEN regulation underlies both

“…The PTEN gene was originally identified by three independent groups using different methodologies: a representational difference analysis of tumours; a high-density scan of chromosome 10q in glioma cell lines and a screening of human cDNA libraries designed to detect protein phosphatases upregulated in response to transforming growth factor b (TGF-b) (Maehama et al, 2001). Mutations and deletions in the PTEN locus were subsequently found to be associated with a broad range of human cancers.…”

“…The translation product is a 53 kDa protein with extensive homology to tensin/auxilin and protein tyrosine phosphatases (PTPs). Studies of the crystal structure of PTEN have revealed an enlarged catalytic site (relative to other PTPs) that accommodates large phosphoinositide substrates, and a C2 domain that mediates the recruitment of proteins to the membrane (Maehama et al, 2001). In addition to the C2 domain, the C-terminus of PTEN contains a PSD95/SAP90, DLG, ZO-1 (PDZ)-binding domain (involved in protein -protein interactions) and two proline, glutamic acid, serine and threonine (PEST) sequences (involved in protein degradation) (Leslie and Downes, 2004).…”

“…However, PTEN removes phosphate groups from phosphorylated threonine and serine protein targets only very inefficiently, and its lipid phosphatase activity is now considered its most important attribute. PTEN is most active against negatively charged peptides, and its primary cellular substrate is the membrane lipid phosphoinositide-3,4,5-trisphosphate (PIP 3 ) (Maehama et al, 2001). Phosphatidylinositol 3,4,5-trisphosphate is the principal second messenger of the phosphoinositide-3 kinase (PI3 0 K) pathway that mediates receptor tyrosine kinase signalling through to the survival kinase PKB/Akt (Chan et al, 1999).…”

“…Activated PKB/Akt transfers a phosphate group to target proteins involved in cell survival, cell cycling and metabolism (Chan et al, 1999). PTEN exerts its tumour-suppressive effect by dephosphorylating PIP 3 , thereby negatively regulating PKB/Akt activation and the PI3 0 K survival pathway (Maehama et al, 2001).…”

“…Engineered overexpression of PTEN induces profound growth suppression primarily by promoting cell cycle arrest. For example, PTEN overexpression leads to G1 arrest in glioma, breast, endometrial and prostate cancer cells (Maehama et al, 2001). This cell cycle arrest requires PTEN's lipid phosphatase activity, can be enhanced by low serum, and can be rescued with the introduction of constitutively active forms of PI3 0 K, PKB/Akt or PDK-1 (Maehama et al, 2001).…”