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PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis
A Besson1, S M Robbins, V W Yong
1Department of Oncology, University of Calgary, Alberta, Canada.
Abstract:
The level of phosphorylation within cells is tightly regulated by the concerted action of protein kinases and protein phosphatases [Hunter, T. (1995) Cell 80, 225-236]. Disregulation in the activity of either of these players can lead to cellular transformation. Many protein tyrosine kinases are proto-oncogenes and it has been postulated that some protein phosphatases may act as tumor suppressors. Herein we will review the recent findings addressing the roles the candidate tumor suppressor PTEN/MMAC1/TEP1 (PTEN, phosphatase and tensin homologue deleted from chromosome 10; MMAC 1, mutated in multiple advanced cancers 1; TEP1, TGF beta regulated and epithelial cell enriched phosphatase 1) plays in signal transduction and tumorigenesis. PTEN is a dual specificity protein phosphatase (towards phospho-Ser/Thr and phospho-Tyr) and, unexpectedly, also has a phosphoinositide 3-phosphatase activity. PTEN plays an important role in the modulation of the 1-phosphatidylinositol 3-kinase (PtdIns 3-kinase) pathway, by catalyzing the degradation of the PtdIns(3,4,5)P3 generated by PtdIns 3-kinase; this inhibits the downstream functions mediated by the PtdIns 3-kinase pathway, such as activation of protein kinase B (PKB, also known as Akt), cell survival and cell proliferation. Furthermore, PTEN modulates cell migration and invasion by negatively regulating the signals generated at the focal adhesions, through the direct dephosphorylation and inhibition of focal adhesion kinase (FAK). Growth factor receptor signaling is also negatively regulated by PTEN, through the inhibition of the adaptor protein Shc. While some of the functions of PTEN have been elucidated, it is clear that there is much more to discover about the roles of this unique protein.
Insights
The tumor suppressor PTEN (phosphatase and tensin homologue deleted from chromosome 10) regulates cell signaling pathways. It dephosphorylates key molecules, inhibiting cell growth, survival, and migration, thus impacting tumorigenesis.
Area of Science:
- Cellular Biology
- Molecular Biology
- Oncology
Background:
- Cellular phosphorylation is regulated by protein kinases and phosphatases.
- Dysregulation of these enzymes can lead to cellular transformation and cancer.
- Some protein phosphatases are hypothesized to function as tumor suppressors.
Purpose of the Study:
- To review recent findings on the roles of the candidate tumor suppressor PTEN (phosphatase and tensin homologue deleted from chromosome 10) in signal transduction and tumorigenesis.
- To elucidate the multifaceted functions of PTEN in cellular processes.
Main Methods:
- Literature review of PTEN's involvement in cellular signaling pathways.
- Analysis of PTEN's phosphatase activities (dual specificity and phosphoinositide).
- Examination of PTEN's regulatory effects on key signaling molecules and pathways.
Main Results:
- PTEN is a dual specificity phosphatase with phosphoinositide 3-phosphatase activity.
- PTEN dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), inhibiting the phosphatidylinositol 3-kinase (PtdIns 3-kinase) pathway.
- PTEN negatively regulates protein kinase B (PKB/Akt), cell survival, proliferation, migration, invasion, focal adhesion kinase (FAK), and growth factor receptor signaling via Shc.
Conclusions:
- PTEN plays a critical role in modulating crucial cellular pathways, including the PtdIns 3-kinase/PKB pathway.
- PTEN's functions extend to regulating cell migration, invasion, and growth factor signaling.
- Further research is needed to fully understand the complex roles of PTEN in cellular processes and disease.