PathFinder Cell Signaling Pathway

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PTEN Pathway
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 PTEN Pathway

PTEN, phosphatase and tensin homolog (TEP1), is a dual specificity protein/3-lipid phosphatase that functions as a tumor suppressor and negative growth regulator. Inactivation of PTEN is associated with a variety cancers including glioblastoma, melanoma, and prostate, breast, and endometrial cancers.

Under normal conditions, PTEN down-regulates the effects of PI3-kinase activity mediated through the formation of PtdIns(3,4,5) trisphosphate. PTEN (TEP1), as a lipid phosphatase, dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (PIP2), the substrate for PI-phospholipase C. PtdIns(3,4,5)P3 and it’s dephosphorylated product PtdIns(3,4) bisphosphate, formed by 5’-lipid phosphatases, such as Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP), are membrane associated lipids that regulate cell processes that promote survival, growth, mitosis, protein synthesis, and motility. These lipids promote cell membrane association and activation of a variety of kinase and lipases that contain peckstrin homology (PH) domains. A large number of signaling molecules are regulated through PH domains and PtdIns(3,4,5) trisphosphate and PtdIns(3,4) bisphosphate. The specific signals depend upon the cell type and context but generally include members of the following families: phosphoinositide-dependent kinases (PDK1), Akt/PKB, p70S6K, various GEFs, Bruton’s protein kinase (Btk), integrin-linked kinase (ILK), atypical protein kinases C (PKC), centaurin-1, Gab-1, DOS and phospholipase Cgamma.

PTEN, as a protein phosphatase, can dephosphorylate focal adhesion kinase-1 (FAK) and interrupt focal adhesion complex (FAC)-associated growth factor and integrin signaling leading to growth and survival. PTEN dephosphorylation of FAK promotes apoptosis in response to cell detachment from the extracellular matrix (ECM). Consequently, defects in PTEN activity may contribute increased tumor invasiveness.

References:

    Currie, R.A. et. al. (1999) Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem. J. 337, 575-583. Cai, X.M. et. al. (2005) Protein phosphatase activity of PTEN inhibited the invasion of glioma cells with epidermal growth factor receptor mutation type III expression. Int. J. Cancer. 117, 905-912.

    Tamura, M. et. al. (1999) PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. J. Biol. Chem. 274, 20693-20703.

    Franke, T.F. et. al. (1007) Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science. 275, 665-668

    Freeburn, R.W. et. al. (2002) Evidence that SHIP-1 contributes to phosphatidylinositol 3,4,5-trisphosphate metabolism in T lymphocytes and can regulate novel phosphoinositide 3-kinase effectors. J. Immunol. 169, 5441-5450.

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Content for this page is provided by Dennis R. Conrad, Ph.D., a Life Science industry consultant with over 25 years of experience in the formulation and optimization of cell culture media. Dr. Conrad's email address is biomediaexpert@earthlink.net