UC San Diego
Investigating the Role of K63-linked Polyubiquitination in Oncogenic IKKβ and BRAF Mutants
- Author(s): Cardenas, Guillermo
- Advisor(s): Donoghue, Daniel J.
- et al.
Aberrant signaling from mutations at K171 in the kinase domain of IKKΒ is known to occur in multiple myeloma, spleen marginal zone lymphoma, and mantle cell lymphoma. Previous work demonstrated that constitutive kinase activation stimulates Signal Transducer and Activator of Transcription 3 (STAT3). Using mass spectrometry, we identified K147 as a site for K63-linked ubiquitination that only occurs in mutant IKKB K171E. The crosstalk between this IKKβ mutant and the Janus Kinases (JAKs) pathway was further investigated by using a IL-6-responsive cell line, which showed that IKKβ 171E mutants stimulates the release of IL-6 into conditioned media. This suggests that it triggers an autocrine loop in which IL-6 is secreted and binds to its own IL-6 receptor-gp130 complex, resulting in JAK activation. Lastly, proteins associated with K63-only-ubiquitinated IKKβ K171E were examined using mass spectrometry, and using proteomic analysis, activation of proteins and pathways involved in proliferative responses were found. Knowing that cancers harboring the K171E mutation on IKKβ can also activate STAT3 along with p44/42 MAPK (Erk1/2), the possibility of using MAPK and JAK inhibitors, or specific ubiquitination inhibitors as treatments should be investigated.