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PHLPP2 suppresses the NF-?B pathway by inactivating IKK? kinase.

ABSTRACT: The NF-?B growth pathway is constitutively activated in many cancers but its activation mechanism is unclear in most cases. We show that PHLPP2 interacts with IKK? kinase, decreases its phosphorylation and the subsequent NF-?B activation in cancer cells. PHLPP2 is progressively lost in glioma and colorectal cancer and acts as a bona fide tumor suppressor, depending on IKK? expression in cells. Physiologically, IKK? activation by growth factors requires the formation of the Bcl10-MALT1 ubiquitin-ligase complex leading to NEMO/IKK? non-degradative ubiquitination and IKK? 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 IKK? phosphorylation, resulting in increased NF-?B-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-?B signaling.

SUBMITTER: Agarwal NK 

PROVIDER: S-EPMC3996652 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase.

Agarwal Nitin Kumar NK   Zhu Xiaoping X   Gagea Mihai M   White Charles L CL   Cote Gilbert G   Georgescu Maria-Magdalena MM  

Oncotarget 20140201 3

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-  ...[more]

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