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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Autophagy-Related Protein 8 Family
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Microfilament Proteins / metabolism
  • Microtubule-Associated Proteins / chemistry
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Conformation
  • Protein Multimerization
  • Signal Transduction
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Ubiquitination
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Protein 8 Family
  • CUL3 protein, human
  • Cullin Proteins
  • GABARAP protein, human
  • GABARAPL2 protein, human
  • Guanine Nucleotide Exchange Factors
  • KBTBD6 protein, human
  • KBTBD7 protein, human
  • Microfilament Proteins
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • RAC1 protein, human
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • TIAM1 protein, human
  • Trans-Activators
  • rac1 GTP-Binding Protein

Associated data

  • PDB/4XC2