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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

Summary of regulation mechanisms for PTEN critical for its action in developmental biology. PTEN transcription is regulated by TGFβ, BMP, Hh, NOTCH, and cytokine signaling in cells during development. miRNAs and ceRNAs regulate PTEN message stability. Phosphorylation or acetylation by then can regulate PTEN's protein stability, enzymatic activity, and cellular localization in a positive or negative manner. All told, the regulation of PTEN is complex and precise during development, and perturbations in this paradigm have profound effects.
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fig3: Summary of regulation mechanisms for PTEN critical for its action in developmental biology. PTEN transcription is regulated by TGFβ, BMP, Hh, NOTCH, and cytokine signaling in cells during development. miRNAs and ceRNAs regulate PTEN message stability. Phosphorylation or acetylation by then can regulate PTEN's protein stability, enzymatic activity, and cellular localization in a positive or negative manner. All told, the regulation of PTEN is complex and precise during development, and perturbations in this paradigm have profound effects.

Mentions: Most studies evaluating the role of PTEN in human diseases have been centered upon mutation in PTEN itself, and most of this work is done in its relationship to cancer initiation and progression. There is no question that mutations of PTEN play a critical role in this regard. Studies over the last decade, however, have discovered a tremendous diversity in the regulation of PTEN expression and found that PTEN is tightly controlled both transcriptionally and posttranscriptionally [67]. Recent studies to date have implicated microRNAs in PTEN suppression [68], and the enzymatic phosphatase activity of PTEN is also regulated posttranslationally via phosphorylation, ubiquitination, or oxidation [69, 70]. This section highlights the multifaceted mechanisms of PTEN regulation, supported by the rapidly expanding literature on PTEN's role in growth and patterning of tissues during development. In addition, special emphasis is given to mediators and pathways involved in development including insulin-like growth factor, transforming growth factor, bone morphogenetic proteins, NOTCH, forkhead transcription factors (Fox), and others. PTEN's complex regulation at the levels of transcription, mRNA stability, posttranslational modifications, and miRNA levels has become a critical series of mechanisms deserving a comprehensive review (for an overview, see Figure 3).


Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling.

Jerde TJ - J Signal Transduct (2015)

Summary of regulation mechanisms for PTEN critical for its action in developmental biology. PTEN transcription is regulated by TGFβ, BMP, Hh, NOTCH, and cytokine signaling in cells during development. miRNAs and ceRNAs regulate PTEN message stability. Phosphorylation or acetylation by then can regulate PTEN's protein stability, enzymatic activity, and cellular localization in a positive or negative manner. All told, the regulation of PTEN is complex and precise during development, and perturbations in this paradigm have profound effects.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Summary of regulation mechanisms for PTEN critical for its action in developmental biology. PTEN transcription is regulated by TGFβ, BMP, Hh, NOTCH, and cytokine signaling in cells during development. miRNAs and ceRNAs regulate PTEN message stability. Phosphorylation or acetylation by then can regulate PTEN's protein stability, enzymatic activity, and cellular localization in a positive or negative manner. All told, the regulation of PTEN is complex and precise during development, and perturbations in this paradigm have profound effects.
Mentions: Most studies evaluating the role of PTEN in human diseases have been centered upon mutation in PTEN itself, and most of this work is done in its relationship to cancer initiation and progression. There is no question that mutations of PTEN play a critical role in this regard. Studies over the last decade, however, have discovered a tremendous diversity in the regulation of PTEN expression and found that PTEN is tightly controlled both transcriptionally and posttranscriptionally [67]. Recent studies to date have implicated microRNAs in PTEN suppression [68], and the enzymatic phosphatase activity of PTEN is also regulated posttranslationally via phosphorylation, ubiquitination, or oxidation [69, 70]. This section highlights the multifaceted mechanisms of PTEN regulation, supported by the rapidly expanding literature on PTEN's role in growth and patterning of tissues during development. In addition, special emphasis is given to mediators and pathways involved in development including insulin-like growth factor, transforming growth factor, bone morphogenetic proteins, NOTCH, forkhead transcription factors (Fox), and others. PTEN's complex regulation at the levels of transcription, mRNA stability, posttranslational modifications, and miRNA levels has become a critical series of mechanisms deserving a comprehensive review (for an overview, see Figure 3).

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