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Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling.

Jerde TJ - J Signal Transduct (2015)

Bottom Line: In numerous cell types, PTEN loss-of-function mutations result in unopposed Akt signaling, producing numerous effects on cells.Specifically, a focus is placed on the role developmental signaling pathways play in PTEN regulation; this includes insulin-like growth factor, NOTCH, transforming growth factor, bone morphogenetic protein, wnt, and hedgehog signaling.The regulation of PTEN by developmental mediators affects critical biological processes including neuronal and organ development, stem cell maintenance, cell cycle regulation, inflammation, response to hypoxia, repair and recovery, and cell death and survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, IU-Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA.

ABSTRACT
Phosphatase and tensin homologue (PTEN) is a critical cell endogenous inhibitor of phosphoinositide signaling in mammalian cells. PTEN dephosphorylates phosphoinositide trisphosphate (PIP3), and by so doing PTEN has the function of negative regulation of Akt, thereby inhibiting this key intracellular signal transduction pathway. In numerous cell types, PTEN loss-of-function mutations result in unopposed Akt signaling, producing numerous effects on cells. Numerous reports exist regarding mutations in PTEN leading to unregulated Akt and human disease, most notably cancer. However, less is commonly known about nonmutational regulation of PTEN. This review focuses on an emerging literature on the regulation of PTEN at the transcriptional, posttranscriptional, translational, and posttranslational levels. Specifically, a focus is placed on the role developmental signaling pathways play in PTEN regulation; this includes insulin-like growth factor, NOTCH, transforming growth factor, bone morphogenetic protein, wnt, and hedgehog signaling. The regulation of PTEN by developmental mediators affects critical biological processes including neuronal and organ development, stem cell maintenance, cell cycle regulation, inflammation, response to hypoxia, repair and recovery, and cell death and survival. Perturbations of PTEN regulation consequently lead to human diseases such as cancer, chronic inflammatory syndromes, developmental abnormalities, diabetes, and neurodegeneration.

No MeSH data available.


Related in: MedlinePlus

Protein domains of PTEN. PTEN has five distinct domains, consisting of an N-terminal PIP binding domain, the phosphatase domain responsible for its enzymatic activity and containing acetylation sites responsible for regulating this phosphatase activity, the regulatory C2 domain responsible for its cellular location and protein-protein interactions including those that modify enzyme activity or localization, the less understood C-tail containing phosphorylation sites thought to be critical for PTEN's stability, and finally the C-terminal PDZ domain.
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fig1: Protein domains of PTEN. PTEN has five distinct domains, consisting of an N-terminal PIP binding domain, the phosphatase domain responsible for its enzymatic activity and containing acetylation sites responsible for regulating this phosphatase activity, the regulatory C2 domain responsible for its cellular location and protein-protein interactions including those that modify enzyme activity or localization, the less understood C-tail containing phosphorylation sites thought to be critical for PTEN's stability, and finally the C-terminal PDZ domain.

Mentions: Phosphatase and tensin homolog (PTEN) is a ubiquitously expressed protein that functions as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3 or PIP3) by catalyzing the dephosphorylation of the 3′ phosphate of the inositol ring in PIP3 [1]. The resulting product of this reaction is the biphosphate product PIP2 (PtdIns(4,5)P2). Since PIP3 is a primary activator of the signaling intermediate Akt, dephosphorylation of PIP3 by PTEN results in inhibition of the AKT signaling pathway. Akt is a serine/threonine-specific protein kinase that is critical for many cellular functions including cell proliferation, apoptosis, transcription, and cell migration and structure [1]. PTEN also functions as a protein phosphatase by dephosphorylating proteins including focal adhesion kinase in the cytosol and Erk, histone H1, RAD51, and CENC-P in the nucleus. Therefore, PTEN has effects on cell migration via integrin signaling, chromatin remodeling through its interactions with histones, cell cycle progression and arrest independent of Akt signaling, DNA repair via its modulation of RAD51, and centrosome stability via its role with CENC-P. PTEN's structure, described in Figure 1, consists of a phosphatase domain harboring the active site and enzymatic function of the protein and a C2 domain responsible for the phospholipid membrane binding site [2]. As such, the C2 domain is responsible for cellular location and allows PTEN localization to membrane-bound PIP3; this promotes PTEN's phosphoinositide phosphatase function by locating it to the cellular location of its substrates [2]. The functions of the C-terminal and PDZ domains are less defined [2].


Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling.

Jerde TJ - J Signal Transduct (2015)

Protein domains of PTEN. PTEN has five distinct domains, consisting of an N-terminal PIP binding domain, the phosphatase domain responsible for its enzymatic activity and containing acetylation sites responsible for regulating this phosphatase activity, the regulatory C2 domain responsible for its cellular location and protein-protein interactions including those that modify enzyme activity or localization, the less understood C-tail containing phosphorylation sites thought to be critical for PTEN's stability, and finally the C-terminal PDZ domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4539077&req=5

fig1: Protein domains of PTEN. PTEN has five distinct domains, consisting of an N-terminal PIP binding domain, the phosphatase domain responsible for its enzymatic activity and containing acetylation sites responsible for regulating this phosphatase activity, the regulatory C2 domain responsible for its cellular location and protein-protein interactions including those that modify enzyme activity or localization, the less understood C-tail containing phosphorylation sites thought to be critical for PTEN's stability, and finally the C-terminal PDZ domain.
Mentions: Phosphatase and tensin homolog (PTEN) is a ubiquitously expressed protein that functions as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3 or PIP3) by catalyzing the dephosphorylation of the 3′ phosphate of the inositol ring in PIP3 [1]. The resulting product of this reaction is the biphosphate product PIP2 (PtdIns(4,5)P2). Since PIP3 is a primary activator of the signaling intermediate Akt, dephosphorylation of PIP3 by PTEN results in inhibition of the AKT signaling pathway. Akt is a serine/threonine-specific protein kinase that is critical for many cellular functions including cell proliferation, apoptosis, transcription, and cell migration and structure [1]. PTEN also functions as a protein phosphatase by dephosphorylating proteins including focal adhesion kinase in the cytosol and Erk, histone H1, RAD51, and CENC-P in the nucleus. Therefore, PTEN has effects on cell migration via integrin signaling, chromatin remodeling through its interactions with histones, cell cycle progression and arrest independent of Akt signaling, DNA repair via its modulation of RAD51, and centrosome stability via its role with CENC-P. PTEN's structure, described in Figure 1, consists of a phosphatase domain harboring the active site and enzymatic function of the protein and a C2 domain responsible for the phospholipid membrane binding site [2]. As such, the C2 domain is responsible for cellular location and allows PTEN localization to membrane-bound PIP3; this promotes PTEN's phosphoinositide phosphatase function by locating it to the cellular location of its substrates [2]. The functions of the C-terminal and PDZ domains are less defined [2].

Bottom Line: In numerous cell types, PTEN loss-of-function mutations result in unopposed Akt signaling, producing numerous effects on cells.Specifically, a focus is placed on the role developmental signaling pathways play in PTEN regulation; this includes insulin-like growth factor, NOTCH, transforming growth factor, bone morphogenetic protein, wnt, and hedgehog signaling.The regulation of PTEN by developmental mediators affects critical biological processes including neuronal and organ development, stem cell maintenance, cell cycle regulation, inflammation, response to hypoxia, repair and recovery, and cell death and survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, IU-Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA.

ABSTRACT
Phosphatase and tensin homologue (PTEN) is a critical cell endogenous inhibitor of phosphoinositide signaling in mammalian cells. PTEN dephosphorylates phosphoinositide trisphosphate (PIP3), and by so doing PTEN has the function of negative regulation of Akt, thereby inhibiting this key intracellular signal transduction pathway. In numerous cell types, PTEN loss-of-function mutations result in unopposed Akt signaling, producing numerous effects on cells. Numerous reports exist regarding mutations in PTEN leading to unregulated Akt and human disease, most notably cancer. However, less is commonly known about nonmutational regulation of PTEN. This review focuses on an emerging literature on the regulation of PTEN at the transcriptional, posttranscriptional, translational, and posttranslational levels. Specifically, a focus is placed on the role developmental signaling pathways play in PTEN regulation; this includes insulin-like growth factor, NOTCH, transforming growth factor, bone morphogenetic protein, wnt, and hedgehog signaling. The regulation of PTEN by developmental mediators affects critical biological processes including neuronal and organ development, stem cell maintenance, cell cycle regulation, inflammation, response to hypoxia, repair and recovery, and cell death and survival. Perturbations of PTEN regulation consequently lead to human diseases such as cancer, chronic inflammatory syndromes, developmental abnormalities, diabetes, and neurodegeneration.

No MeSH data available.


Related in: MedlinePlus