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PTEN, NHERF1 and PHLPP form a tumor suppressor network that is disabled in glioblastoma
J R Molina1, N K Agarwal, F C Morales
1Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
The phosphatidylinositol-3-OH kinase (PI3K)-Akt pathway is activated in cancer by genetic or epigenetic events and efforts are under way to develop targeted therapies. phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is the major brake of the pathway and a common target for inactivation in glioblastoma, one of the most aggressive and therapy-resistant cancers. To achieve potent inhibition of the PI3K-Akt pathway in glioblastoma, we need to understand its mechanism of activation by investigating the interplay between its regulators. We show here that PTEN modulates the PI3K-Akt pathway in glioblastoma within a tumor suppressor network that includes Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) and pleckstrin-homology domain leucine-rich repeat protein phosphatases 1 (PHLPP1). The NHERF1 adaptor, previously characterized by our group as a PTEN ligand and regulator, shows also PTEN-independent Akt-modulating effects that led us to identify the PHLPP1/PHLPP2 Akt phosphatases as NHERF1 ligands. NHERF1 interacts via its PDZ domains with PHLPP1/PHLPP2 and scaffolds heterotrimeric complexes with PTEN. Functionally, PHLPP1 requires NHERF1 for membrane localization and growth-suppressive effects. PHLPP1 loss boosts Akt phosphorylation only in PTEN-negative cells and cooperates with PTEN loss for tumor growth. In a panel of low-grade and high-grade glioma patient samples, we show for the first time a significant disruption of all three members of the PTEN-NHERF1-PHLPP1 tumor suppressor network in high-grade tumors, correlating with Akt activation and patient's abysmal survival. We thus propose a PTEN-NHERF1-PHLPP PI3K-Akt pathway inhibitory network that relies on molecular interactions and can undergo parallel synergistic hits in glioblastoma.
Insights
A tumor suppressor network involving PTEN, NHERF1, and PHLPP1 regulates the PI3K-Akt pathway in glioblastoma. Disruption of this network correlates with aggressive tumors and poor survival, offering therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The phosphatidylinositol-3-OH kinase (PI3K)-Akt pathway is frequently activated in cancers, including glioblastoma, driving tumor growth and therapy resistance.
- The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a key tumor suppressor that inhibits the PI3K-Akt pathway and is often inactivated in glioblastoma.
Purpose of the Study:
- To elucidate the regulatory mechanisms of the PI3K-Akt pathway in glioblastoma by investigating the interplay between its regulators.
- To identify novel components and interactions within a PTEN-centered tumor suppressor network that controls Akt activity.
Main Methods:
- Investigated protein-protein interactions using co-immunoprecipitation and identified ligands for Na(+)/H(+) exchanger regulatory factor 1 (NHERF1).
- Assessed the functional roles of PHLPP1 and NHERF1 in Akt phosphorylation and cell growth.
- Analyzed the expression and correlation of PTEN, NHERF1, and PHLPP1 in patient glioma samples.
Main Results:
- Identified pleckstrin-homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/PHLPP2) as NHERF1 ligands, forming a complex with PTEN.
- Demonstrated that NHERF1 is required for PHLPP1 membrane localization and tumor-suppressive function.
- Observed a significant disruption of the PTEN-NHERF1-PHLPP1 network in high-grade gliomas, correlating with increased Akt phosphorylation and reduced patient survival.
Conclusions:
- Established a PTEN-NHERF1-PHLPP1 tumor suppressor network that inhibits the PI3K-Akt pathway in glioblastoma.
- This network's integrity is crucial for controlling Akt activity and tumor progression.
- Disruption of this network represents a critical event in glioblastoma pathogenesis and suggests potential therapeutic strategies targeting these interactions.
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