F-Box Only Protein 31 (FBXO31) Negatively Regulates p38 Mitogen-Activated Protein (MAP) Kinase Signaling by Mediating Lysine 48-Linked Ubiquitination and Degradation of MAP Kinase Kinase 6 (MKK6).

The p38 mitogen-activated protein (MAP) kinase signal transduction pathway plays an important role in inflammatory and stress responses. MAP Kinase Kinase 6 (MKK6), a dual specificity protein kinase, is a p38 activator. Activation of the MKK6-p38 pathway is kept in check by multiple layers of regulations, including autoinhibition, dimerization, scaffold ...
proteins and lysine 63 (K63)-linked polyubiquitination. However, the mechanisms underlying deactivation of MKK6-p38, which is crucial for maintaining magnitude and duration of signal transduction, are not well understood. Lysine 48 (K48)-linked ubiquitination, which marks substrates for proteasomal degradation, is an important negative post-translational regulatory machinery for signal pathway transduction. Here we report that the accumulation of F-box only protein 31 (FBXO31), a component of Skp1-Cul1-F-box protein (SCF) E3 ligase, negatively regulated p38 activation in cancer cells upon genotoxic stresses. Our results showed that FBXO31 binds to MKK6 and mediates its K48-linked polyubiquitination and degradation, thereby functioning as a negative regulator of MKK6-p38 signaling and protecting cells from stress-induced cell apoptosis. Taken together, our findings uncover a new mechanism of deactivation of MKK6/p38, and substantiate a novel regulatory role of FBXO31 in stress response.
J. Biol. Chem.
Date: Jun. 16, 2014
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