Regulation of Cell Migration by the C2 Domain of the Tumor Suppressor PTEN

Raftopoulou, Myrto; Etienne-Manneville, Sandrine; Self, Annette J.; Nicholls, Sarah; Hall, Alan

doi:10.1126/science.1092089

Cited by 305 publications

(324 citation statements)

References 21 publications

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“…Recent work indicates that interference with the activity of Na,K-ATPase may be a useful strategy to treat some forms of breast cancer (Chen et al, 2006). Interestingly, overexpression of PTEN can revert the migratory phenotype in glioblastoma cells (Raftopoulou et al, 2004), although in this case it is the protein phosphatase (and not the lipid phosphatase) function of PTEN that is responsible for this change.…”

Section: Hijacking Of the Domain-identity Machinerymentioning

confidence: 99%

The epithelial polarity program: machineries involved and their hijacking by cancer

2008

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The Epithelial Polarity Program (EPP) adapts and integrates three ancient cellular machineries to construct an epithelial cell. The polarized trafficking machinery adapts the cytoskeleton and ancestral secretory and endocytic machineries to the task of sorting and delivering different plasma membrane (PM) proteins to apical and basolateral surface domains. The domain-identity machinery builds a tight junctional fence (TJ) between apical and basolateral PM domains and adapts ancient polarity proteins and polarity lipids on the cytoplasmic side of the PM, which have evolved to perform a diversity of polarity tasks across cells and species, to provide 'identity' to each epithelial PM domain. The 3D organization machinery utilizes adhesion molecules as positional sensors of other epithelial cells and the basement membrane and small GTPases as integrators of positional information with the activities of the domain-identity and polarized trafficking machineries. Cancer is a disease mainly of epithelial cells (90% of human cancers are carcinomas that derive from epithelial cells) that hijacks the EPP machineries, resulting in loss of epithelial polarity, which often correlates in extent with the aggressiveness of the tumor. Here, we review how the EPP integrates its three machineries and the strategies used by cancer to hijack them.

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Section: Hijacking Of the Domain-identity Machinerymentioning

confidence: 99%

The epithelial polarity program: machineries involved and their hijacking by cancer

2008

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“…Indeed, the PTP activity of PTEN has been implicated in cellular processes such as cell motility (Raftopoulou et al, 2004). However, PTEN removes phosphate groups from phosphorylated threonine and serine protein targets only very inefficiently, and its lipid phosphatase activity is now considered its most important attribute.…”

Section: Functions Of the Pten Proteinmentioning

confidence: 99%

Tumours and tremors: how PTEN regulation underlies both

Kim

Mak

2006

Br J Cancer

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“…These include a poorly characterized protein phosphatase activity and proposed nonenzymatic mechanisms such as interaction with other proteins. [7][8][9] Recent advances have also proved the importance of PTEN subcellular localization. Localized PTEN activity appears to establish PIP3 signal gradients that regulate cell polarity during motility.…”

mentioning

confidence: 99%

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

et al. 2013

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The tumor suppressor activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10) is thought to be largely attributable to its lipid phosphatase activity. PTEN dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate to directly antagonize the phosphoinositide 3-kinase-Akt pathway and prevent the activating phosphorylation of Akt. PTEN has also other proposed mechanisms of action, including a poorly characterized protein phosphatase activity, protein-protein interactions, as well as emerging functions in different compartment of the cells such as nucleus and mitochondria. We show here that a fraction of PTEN protein localizes to the endoplasmic reticulum (ER) and mitochondriaassociated membranes (MAMs), signaling domains involved in calcium ( 2 þ ) transfer from the ER to mitochondria and apoptosis induction. We demonstrate that PTEN silencing impairs ER Ca 2 þ release, lowers cytosolic and mitochondrial Ca 2 þ transients and decreases cellular sensitivity to Ca 2 þ -mediated apoptotic stimulation. Specific targeting of PTEN to the ER is sufficient to enhance ER-to-mitochondria Ca 2 þ transfer and sensitivity to apoptosis. PTEN localization at the ER is further increased during Ca 2 þ -dependent apoptosis induction. Importantly, PTEN interacts with the inositol 1,4,5-trisphosphate receptors (IP3Rs) and this correlates with the reduction in their phosphorylation and increased Ca 2 þ release. We propose that ER-localized PTEN regulates Ca 2 þ release from the ER in a protein phosphatase-dependent manner that counteracts Akt-mediated reduction in Ca 2 þ release via IP3Rs. These findings provide new insights into the mechanisms and the extent of PTEN tumor-suppressive functions, highlighting new potential strategies for therapeutic intervention.

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Regulation of Cell Migration by the C2 Domain of the Tumor Suppressor PTEN

Cited by 305 publications

References 21 publications

The epithelial polarity program: machineries involved and their hijacking by cancer

The epithelial polarity program: machineries involved and their hijacking by cancer

Tumours and tremors: how PTEN regulation underlies both

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

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