The PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene encodes a plasma membrane lipid phosphatase that is recurrently lost in various human cancers. Heterozygous mutation of PTEN is causative for familial diseases including Cowden syndrome, which is characterized by multiple hamartomas, developmental defects, and increased cancer susceptibility. The major tumor-suppressive activity of PTEN is attributed to its ability to hydrolyze the 3′ phosphate of phosphoinositides at the plasma membrane and thereby negatively regulate phosphoinositide 3-kinase (PI3K) signaling, a promoter of cell growth and survival. In mouse models, Pten is haploinsufficient for tumor suppression. Progressive reduction of Pten dose is also associated with more aggressive cancers in the mouse, leading to the notion that subtle variations in Pten levels could have critical consequences for tumor progression. Indeed, in addition to the loss of PTEN function through genetic alterations at the 10q23 locus, emerging lines of evidence demonstrate that PTEN is tightly regulated by transcriptional, posttranscriptional, and posttranslational mechanisms. Recent studies report that PTEN has tumor-suppressive functions from within the nucleus, including the regulation of chromosomal stability, the DNA repair response, and the cell cycle. Aberrant cytoplasmic localization of PTEN is associated with cancer progression, suggesting that the presence of PTEN in the nucleus is required for its tumorsuppressive activity. How PTEN gets in and out of the nucleus is still not completely understood. Nuclear pore-mediated import as well as the monoubiquitination of PTEN can modulate its subcellular compartmentalization, and germline mutations of residues that are ubiquitinated have been associated with the nuclear exclusion of PTEN in cancerous lesions.
SnapShot: PTEN signaling pathways
PANDOLFI DE RINALDIS, Pier Paolo
2008-01-01
Abstract
The PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene encodes a plasma membrane lipid phosphatase that is recurrently lost in various human cancers. Heterozygous mutation of PTEN is causative for familial diseases including Cowden syndrome, which is characterized by multiple hamartomas, developmental defects, and increased cancer susceptibility. The major tumor-suppressive activity of PTEN is attributed to its ability to hydrolyze the 3′ phosphate of phosphoinositides at the plasma membrane and thereby negatively regulate phosphoinositide 3-kinase (PI3K) signaling, a promoter of cell growth and survival. In mouse models, Pten is haploinsufficient for tumor suppression. Progressive reduction of Pten dose is also associated with more aggressive cancers in the mouse, leading to the notion that subtle variations in Pten levels could have critical consequences for tumor progression. Indeed, in addition to the loss of PTEN function through genetic alterations at the 10q23 locus, emerging lines of evidence demonstrate that PTEN is tightly regulated by transcriptional, posttranscriptional, and posttranslational mechanisms. Recent studies report that PTEN has tumor-suppressive functions from within the nucleus, including the regulation of chromosomal stability, the DNA repair response, and the cell cycle. Aberrant cytoplasmic localization of PTEN is associated with cancer progression, suggesting that the presence of PTEN in the nucleus is required for its tumorsuppressive activity. How PTEN gets in and out of the nucleus is still not completely understood. Nuclear pore-mediated import as well as the monoubiquitination of PTEN can modulate its subcellular compartmentalization, and germline mutations of residues that are ubiquitinated have been associated with the nuclear exclusion of PTEN in cancerous lesions.
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