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PTEN-opathies: from biological insights to evidence-based precision medicine
Lamis Yehia, … , Joanne Ngeow, Charis Eng
Lamis Yehia, … , Joanne Ngeow, Charis Eng
Published January 7, 2019
Citation Information: J Clin Invest. 2019;129(2):452-464. https://doi.org/10.1172/JCI121277.
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Review Series

PTEN-opathies: from biological insights to evidence-based precision medicine

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Abstract

The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the “PTEN-opathies.” Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.

Authors

Lamis Yehia, Joanne Ngeow, Charis Eng

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Figure 1

Cytoplasmic and nuclear PTEN signaling.

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Cytoplasmic and nuclear PTEN signaling.
In the cytoplasm, PTEN canonical...
In the cytoplasm, PTEN canonically functions to regulate the PI3K/AKT/mTOR signaling pathway. Under growth factor stimulation, PI3K is activated and catalyzes the phosphorylation of PIP2 to PIP3. PIP3 recruits PDK1 to the plasma membrane, which then contributes to the activation of AKT. AKT regulates a myriad of downstream cellular processes such as cell growth, proliferation, and decreased apoptosis. The lipid phosphatase activity of PTEN counteracts PI3K by dephosphorylating PIP3 to PIP2, thereby dampening AKT activation. In the nucleus, PTEN plays a vital role in maintaining genomic stability, chromosomal architecture, cell cycle control, and the regulation of ribosome biogenesis within nucleoli.
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