Nuclear PTEN promotes chromosome stability and regulates DNA double-strand break restoration. is as a lipid phosphatase that antagonizes phosphatidylinositol 3-kinase (PI3K) signaling [4]. PI3K is definitely a critical node Balaglitazone in a major signaling pathway that regulates malignancy cell growth, survival, and rate of metabolism (Fig. 1). When triggered, PI3K phosphorylates the 3 (D3) position within the inositol ring of phosphatidylinositol (4,5)-bisphosphate (PIP2), which is present on the inner leaflet of the plasma membrane, to produce phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 serves as a second messenger and binds proteins comprising Balaglitazone pleckstrin homology (PH) domains. The recruitment of PH domain-containing proteins such as AKT to the plasma membrane facilitates their activation, and causes downstream signaling cascades. Cytoplasmic PTEN negatively regulates this pathway by dephosphorylating PIP3 at its D3 position, therefore inhibiting downstream kinase activation and avoiding cancer cell growth and survival (Fig. 1 and ref. [5]). Two recent studies have found that there is a translational variant(s) long form of PTEN secreted from cell that can enter neighboring cells. Like cytoplasmic PTEN, secreted PTEN offers lipid phosphatase activity and antagonizes PI3K signaling in target cells [6, 7]. Open in a separate windowpane Fig. 1 PTEN exhibits tumor suppressive functions in the cytoplasm and nucleusThe phosphatidylinositol 3-kinase (PI3K) pathway regulates malignancy cell growth and survival. This pathway is definitely triggered by ligand binding to receptor tyrosine kinases (RTKs) and/or G protein coupled receptors (GPCRs). PI3K is definitely then recruited to the membrane where it phosphorylates phosphatidylinositol (4,5)-bisphosphate (PIP2) to produce phosphatidylinositol (3,4,5)-trisphosphate (PIP3), leading to activation of several signaling cascades including AKT/mTORC1. Cytoplasmic PTEN negatively regulates this pathway by dephosphorylating PIP3 at its D3 position. Nuclear PTEN promotes chromosome stability and regulates DNA double-strand Balaglitazone break restoration. Red star shows a potential therapeutic target for which a drug(s) is in development. PTEN has also been reported to exhibit protein phosphatase activity. studies showed that PTEN dephosphorylates tyrosine, serine, and threonine residues on phosphopeptides [8]. PTEN interacts with and dephosphorylates focal adhesion kinase and Shc [9, 10]. The protein phosphatase activity of PTEN also reduces cyclin D1 levels, preventing cell cycle progression [11]. Using a fresh bioassay to measure PTEN function in living cells, it was recently demonstrated that PTEN auto-dephosphorylates serine and/or threonine residues in its own C-terminal region; this event(s) appears to promote its lipid phosphatase RICTOR activity [12, 13]. The protein phosphatase activity of PTEN also regulates secretion of hepatitis C disease particles in liver, probably via rules of cholesterol rate of metabolism [14]. While cytoplasmic PTEN is definitely primarily involved in regulating PI3K/PIP3 signaling, nuclear PTEN exhibits phosphatase-independent tumor suppressive functions, including rules of chromosome stability, DNA restoration, and apoptosis (Fig. 1; examined in refs. [15, 16]). Despite the Balaglitazone fact that PTEN lacks a canonical Balaglitazone nuclear localization sequence, ubiquitination in its C-terminal region may promote its nuclear import [17]. Studies in PTEN-null mouse embryonic fibroblasts exposed that 1) nuclear PTEN interacts with Centromere-Specific Binding Protein (CENP-C), an essential component for centromere stability, and 2) PTEN is vital for the induction of RAD51, which regulates DNA double-strand break restoration [18]. Nuclear PTEN binds to the anaphase-promoting complex or cyclosome (APC/C), and heightens the association of APC/C with the co-activator CDC20 homologue 1 (CDH1) [19]. In so doing, PTEN increases the chromosome-stabilizing activity of the APC/C-CDH1 complex [19]. Nuclear PTEN may also promote apoptosis [15]. Human being glioblastoma cells with mainly nuclear PTEN were more likely to have condensed nuclei in response to apoptosis induction, compared to cells with primarily cytoplasmic PTEN [20]. Hence, intracellular localization takes on an important part(s) in the rules of PTEN function(s) [16]. These.
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