PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase
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Nitin Kumar Agarwal1, Xiaoping Zhu1, Mihai Gagea3, Charles L. White 3rd4, Gilbert Cote2 and Maria-Magdalena Georgescu1,4
1 Department of Neuro-Oncology, MD Anderson Cancer Center, Houston, Texas
2 Department of Endocrine Neoplasia, MD Anderson Cancer Center, Houston, Texas
3 Department of Veterinary Medicine, MD Anderson Cancer Center, Houston, Texas
4 Department of Pathology, UT Southwestern Medical Center, Dallas, Texas
Maria-Magdalena Georgescu, email:
Keywords: PHLPP, NF-κB, IKK, glioma, colorectal cancer
Received: January 30, 2014 Accepted: February 13, 2014 Published: February 13, 2014
The NF-κB growth pathway is constitutively activated in many cancers but its activation mechanism is unclear in most cases. We show that PHLPP2 interacts with IKKβ kinase, decreases its phosphorylation and the subsequent NF-κB activation in cancer cells. PHLPP2 is progressively lost in glioma and colorectal cancer and acts as a bona fide tumor suppressor, depending on IKKβ expression in cells. Physiologically, IKKβ activation by growth factors requires the formation of the Bcl10-MALT1 ubiquitin-ligase complex leading to NEMO/IKKγ non-degradative ubiquitination and IKKβ phosphorylation. PHLPP2 opposes the formation of this complex through interaction with Bcl10 and competitive displacement of MALT1 from Bcl10. Conversely, PHLPP2 loss enhances Bcl10-MALT1 complex formation, NEMO ubiquitination and subsequent IKKβ phosphorylation, resulting in increased NF-κB-dependent transcription of multiple target genes. Our results reveal PHLPP2 as a new biomarker of cancer progression, and implicate it as major negative regulator of NF-κB signaling.
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