PTEN phosphatase

All phosphoinositides are found in the cytosolic half of the lipid bilayer of the plasma or intracellular compartment membranes (left part). The different kinases acting on phosphoinositides in mammalian cells are shown in solid lines and the phosphoinositide 3-kinases, in bold. The phosphoinositides counterpart pathways catalysed by known phosphatases are represented by dashed lines. The best known phosphatases are PTEN (Phosphatase and tensin homolog deleted on chromosome 10) and SHIP (SH2 domain-containing inositol 5-phosphatase). 

Phospholipid phosphatases are enzymes such as SHIP (SH2-domain containing inositide-5-phosphatase) or PTEN (phosphatase and tensin homolog deleted on chromosome 10) which dephosphorylate phosphoino-sitides. Whereas SHIP removes phosphate from the 5 ... 

PBD peroxisome biogenesis disorders PTEN phosphatase and tensin homolog... 

PTEN phosphatase and tensin homologue deleted on chromosome 10... 

PTEN, phosphatase and tensin homolog PTPase, phosphotyrosine phosphatase PYY, peptide YY... 

The products of the PI3-kinase reaction are different phosphoinositide derivatives phosphorylated at the 3 position, of which PtdIns(3,4,5)P3 has the greatest regulatory importance. PtIns(3,4,5)P3, like cAMP, has the function of a messenger substance that activates effector molecules in the sequence for further signal conduction. In contrast to cAMP, PtdIns(3,4,5)P3 is localized in the cell membrane and performs its function in close association with processes at the cell membrane. The concentration of PtdIns(3,4,5)P3 in the cell depends both on the rates of synthesis by PI3-kinases and the rates of hydrolysis of its phosphate residues. Several inositol polyphosphate phosphatases have been identified that remove the phosphates at position 3 or 5 of the inositol moiety. Among the inositol polyphosphate phosphatases with specificity for the 3-position, the PTEN phosphatase has been identified as a tumor supressor protein (see below). 

C2 Acidic phospholipids Protein kinase C, PI-3 kinase, phospholipase, PTEN phosphatase... 

PTEN Phosphatase Terminates Signaling via the PI-3 Kinase Pathway... 

Like virtually all intracellular signaling events, phosphorylation by PT3 kinase is reversible. The relevant phosphatase, termed PTEN phosphatase, has an unusually broad specificity. Although PTEN can remove phosphate groups attached to serine, threonine, and tyrosine residues in proteins, its ability to remove the 3-phosphate from PI 3,4,5-trisphosphate is thought to be its major function in cells. Overexpression of PTEN in cultured mammalian cells promotes apoptosis by reducing the level of PI 3,4,5-trisphosphate and hence the activation and anti-apoptotic effect of protein kinase B. 

Signaling via the PT3 kinase pathway Is terminated by the PTEN phosphatase, which hydrolyzes the 3-phosphate in PI 3-phosphates. Loss of PTEN, a common occurrence in human tumors, promotes cell survival and proliferation. 

PI-3 kinase pathway 598 presenllln 1 603 protein kinase B 599 PTEN phosphatase 600 Ras protein 587 receptor tyrosine kinases 578 regulated intramembrane proteolysis 603 scaffold proteins 597 SH2 domains 579 Smads 575... 

Describe the function of the PTEN phosphatase in the PT3 kinase signaling pathway. Why is a loss-of-function mutation in PTEN cancer-promoting Predict the effect of constitutively active PTEN on cell growth and survival. 

Conversely, genes whose protein products stimulate apoptosis behave as tumor suppressors. An example is the PTEN gene discussed In Chapter 14. The phosphatase encoded by this gene dephosphorylates phosphatidyllnositol 3,4,5-trlsphosphate, a second messenger that functions In activation of protein kinase B (see Figure 14-27). Cells lacking PTEN phosphatase have elevated levels of phosphatidyllnositol 3,4,5-trisphosphate and active protein kinase B, which promotes cell survival and prevents apoptosis by several pathways. Thus PTEN acts as a pro-apoptotlc tumor suppressor by decreasing the antl-apoptotic effect of protein kinase B. 

Overproduction of anti-apoptotic proteins (e.g., Bcl-2) can lead to inappropriate cell survival and is associated with chronic lymphoblastic leukemia (CLL) and other cancers. Loss of proteins that promote apoptosis (e.g., p53 transcription factor and PTEN phosphatase) have a similar oncogenic effect. 

Qiao, J., Kang, J., Cree, J., Evers, B. M., Chung, D. H. (2005). Gastrin-releasing peptide-induced down-regulation of tumor suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome ten) in neuroblastomas. Annals of Surgery, 241, 684-691. 

LAST2 - large tumor suppressor 2 PTEN - phosphatase and tensin homolog TPMl - tumor-suppressor tropomyosin-1. 

Figure 50. PTEN. The tumor suppressor gene and gene product protein PTEN (phosphatase tensin homolog deleted on chromosome ten, human 10q23.3) (Table VIII), is the natural inhibitor of oncogenes PI3K/Akt (phosphatidyl inositol kinase 3 protein kinase 3 phosphatidylinositol 3 phosphate Jacob Furth s AK mouse strain thymic lymphoma retroviral oncogene phosphoinosite-dependent kinase). The PTEN protein inactivates PIP3 by dephosphorylation PDKl (phosphoinositol-dependent kinase) is not recruited to the plasma membrane to activate Akt by phosphorylation. Sarah M. Planchon et al. The nuclear affairs of PTEN. J Cell Sci 2008 121 249-253. doi 10.1242/jcs.022459...

---