Genau HM Huber J Baschieri F Akutsu M Dötsch V Farhan H Rogov V Behrends C 2015 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. application/pdf https://sonar.ch/global/documents/279130 eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.molcel.2014.12.040 info:eu-repo/semantics/altIdentifier/pmid/25684205 info:eu-repo/semantics/openAccess Molecular cell. - 2015 Adaptor Proteins, Signal Transducing Amino Acid Sequence Autophagy-Related Protein 8 Family Cullin Proteins Guanine Nucleotide Exchange Factors Humans Microfilament Proteins Microtubule-Associated Proteins Models, Molecular Molecular Sequence Data Multiprotein Complexes Nuclear Magnetic Resonance, Biomolecular Protein Conformation Protein Multimerization Signal Transduction T-Lymphoma Invasion and Metastasis-inducing Protein 1 Trans-Activators Ubiquitination rac1 GTP-Binding Protein CUL3-KBTBD6/KBTBD7 ubiquitin ligase cooperates with GABARAP proteins to spatially restrict TIAM1-RAC1 signaling. http://purl.org/coar/resource_type/c_6501