The TRAF3 adaptor protein drives proliferation of anaplastic large cell lymphoma cells by regulating multiple signaling pathways

Israel Muro, Gloria Fang, Kacie A. Gardella, Indra M. Mahajan, Casey Wright

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

T cells devoid of tumor necrosis factor receptor associated factor-3 (Traf3) exhibit decreased proliferation, sensitivity to apoptosis, and an improper response to antigen challenge. We therefore hypothesized that TRAF3 is critical to the growth of malignant T cells. By suppressing TRAF3 protein in different cancerous T cells, we found that anaplastic large cell lymphoma (ALCL) cells require TRAF3 for proliferation. Since reducing TRAF3 results in aberrant activation of the noncanonical nuclear factor-κB (NF-κB) pathway, we prevented noncanonical NF-κB signaling by suppressing RelB together with TRAF3. This revealed that TRAF3 regulates proliferation independent of the noncanonical NF-κB pathway. However, suppression of NF-κB-inducing kinase (NIK) along with TRAF3 showed that high levels of NIK have a partial role in blocking cell cycle progression. Further investigation into the mechanism by which TRAF3 regulates cell division demonstrated that TRAF3 is essential for continued PI3K/AKT and JAK/STAT signaling. In addition, we found that while NIK is dispensable for controlling JAK/STAT activity, NIK is critical to regulating the PI3K/AKT pathway. Analysis of the phosphatase and tensin homolog (PTEN) showed that NIK modulates PI3K/AKT signaling by altering the localization of PTEN. Together our findings implicate TRAF3 as a positive regulator of the PI3K/AKT and JAK/STAT pathways and reveal a novel function for NIK in controlling PI3K/AKT activity. These results provide further insight into the role of TRAF3 and NIK in T cell malignancies and indicate that TRAF3 differentially governs the growth of B and T cell cancers.

Original languageEnglish (US)
Pages (from-to)1918-1927
Number of pages10
JournalCell Cycle
Volume13
Issue number12
DOIs
StatePublished - Jun 15 2014
Externally publishedYes

Fingerprint

TNF Receptor-Associated Factor 3
Anaplastic Large-Cell Lymphoma
Phosphotransferases
Phosphatidylinositol 3-Kinases
Proteins
T-Lymphocytes
Phosphoric Monoester Hydrolases
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Growth

Keywords

  • JAK/STAT
  • NF-κB
  • NIK
  • PI3K/AKT
  • TRAF3

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

The TRAF3 adaptor protein drives proliferation of anaplastic large cell lymphoma cells by regulating multiple signaling pathways. / Muro, Israel; Fang, Gloria; Gardella, Kacie A.; Mahajan, Indra M.; Wright, Casey.

In: Cell Cycle, Vol. 13, No. 12, 15.06.2014, p. 1918-1927.

Research output: Contribution to journalArticle

Muro, Israel ; Fang, Gloria ; Gardella, Kacie A. ; Mahajan, Indra M. ; Wright, Casey. / The TRAF3 adaptor protein drives proliferation of anaplastic large cell lymphoma cells by regulating multiple signaling pathways. In: Cell Cycle. 2014 ; Vol. 13, No. 12. pp. 1918-1927.
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