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Mol Cell. 2015 Mar 19;57(6):995-1010. doi: 10.1016/j.molcel.2014.12.040. Epub 2015 Feb 12.

CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP proteins to spatially restrict TIAM1-RAC1 signaling.

Author information

1
Institute of Biochemistry II, Goethe University School of Medicine, 60590 Frankfurt am Main, Germany.
2
Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, 60438 Frankfurt am Main, Germany.
3
Department of Biology, University of Konstanz, 78464 Konstanz, Germany; Biotechnology Institute Thurgau, 8280 Kreuzlingen, Switzerland.
4
Buchmann Institute for Molecular Life Sciences, Goethe University, 60438 Frankfurt am Main, Germany.
5
Institute of Biochemistry II, Goethe University School of Medicine, 60590 Frankfurt am Main, Germany. Electronic address: behrends@em.uni-frankfurt.de.

Abstract

The small Rho GTPase RAC1 is an essential regulator of cellular signaling that controls actin rearrangements and cell motility. Here, we identify a novel CUL3 RING ubiquitin ligase complex, containing the substrate adaptors KBTBD6 and KBTBD7, that mediates ubiquitylation and proteasomal degradation of TIAM1, a RAC1-specific GEF. Increasing the abundance of TIAM1 by depletion of KBTBD6 and/or KBTBD7 leads to elevated RAC1 activity, changes in actin morphology, loss of focal adhesions, reduced proliferation, and enhanced invasion. KBTBD6 and KBTBD7 employ ATG8 family-interacting motifs to bind preferentially to GABARAP proteins. Surprisingly, ubiquitylation and degradation of TIAM1 by CUL3(KBTBD6/KBTBD7) depends on its binding to GABARAP proteins. Our study reveals that recruitment of CUL3(KBTBD6/KBTBD7) to GABARAP-containing vesicles regulates the abundance of membrane-associated TIAM1 and subsequently spatially restricted RAC1 signaling. Besides their role in autophagy and trafficking, we uncovered a previously unknown function of GABARAP proteins as membrane-localized signaling scaffolds.

PMID:
25684205
DOI:
10.1016/j.molcel.2014.12.040
[Indexed for MEDLINE]
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