PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase

Nitin Kumar Agarwal, Xiaoping Zhu, Mihai Gagea, Charles L. White, Gilbert Cote, Maria Magdalena Georgescu

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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/IKKβ 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.

Original languageEnglish (US)
Pages (from-to)815-823
Number of pages9
JournalOncotarget
Volume5
Issue number3
StatePublished - 2014

Fingerprint

Phosphotransferases
Ubiquitination
Phosphorylation
Neoplasms
Ligases
Tumor Biomarkers
Ubiquitin
Glioma
Colorectal Neoplasms
Intercellular Signaling Peptides and Proteins
Growth
Genes

Keywords

  • Colorectal cancer
  • Glioma
  • IKK
  • NF-κB
  • PHLPP

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

Cite this

Agarwal, N. K., Zhu, X., Gagea, M., White, C. L., Cote, G., & Georgescu, M. M. (2014). PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase. Oncotarget, 5(3), 815-823.

PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase. / Agarwal, Nitin Kumar; Zhu, Xiaoping; Gagea, Mihai; White, Charles L.; Cote, Gilbert; Georgescu, Maria Magdalena.

In: Oncotarget, Vol. 5, No. 3, 2014, p. 815-823.

Research output: Contribution to journalArticle

Agarwal, NK, Zhu, X, Gagea, M, White, CL, Cote, G & Georgescu, MM 2014, 'PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase', Oncotarget, vol. 5, no. 3, pp. 815-823.
Agarwal NK, Zhu X, Gagea M, White CL, Cote G, Georgescu MM. PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase. Oncotarget. 2014;5(3):815-823.
Agarwal, Nitin Kumar ; Zhu, Xiaoping ; Gagea, Mihai ; White, Charles L. ; Cote, Gilbert ; Georgescu, Maria Magdalena. / PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase. In: Oncotarget. 2014 ; Vol. 5, No. 3. pp. 815-823.
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