Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 316, Issue 1, Pages 139-148Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2004.02.033
Keywords
lung Kruppel-like factor; KLF2; E3-ubiquitin ligase; WWP1; ubiquitination; post-translational modification of Kruppel-like factors
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Funding
- NHLBI NIH HHS [R01 HL 57281] Funding Source: Medline
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The zinc-finger transcription factor Kruppel-like factor-2 plays an important role in pulmonary development, inhibition of adipocyte differentiation, and maintaining quiescence in single-positive T cells. KLF2 levels rapidly decrease during adipogenesis and activation of T cells, but the pathways involved remain unclear. Previously, we identified WWP1, a HECT-domain E3-ubiquitin ligase, as an interacting partner of KLF2. This led us to speculate that KLF2 may be targeted for ubiquitination. Here, we demonstrate that WWP1 interacts with KLF2 in vivo and mediates both poly-ubiquitination and proteasomal degradation of KLF2. Deleting the inhibitory domain of KLF2 abrogated KLF2-WWP1 interactions and abolished WWP1-mediated poly-ubiquitination and down-regulation of KLF2. Furthermore, lysine-121 in the inhibitory domain of KLF2 is critical for ubiquitin-conjugation. Finally, the catalytic cysteine of WWP1 is not required for KLF2-ubiquitination. Our experiments demonstrate for the first time that WWP1 promotes ubiquitination and degradation of KLF2 and is not involved in the ubiquitin-transfer reaction. (C) 2004 Elsevier Inc. All rights reserved.
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