The Cullin-3–Rbx1–KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB

Kovačević, Igor; Sakaue, Tomohisa; Majolée, Jisca; Pronk, Mathilde C.; Maekawa, Mamoru; Geerts, Dirk; Fernandez‐Borja, Mar; Higashiyama, Shigeki; Hordijk, Peter L.

doi:10.1083/jcb.201606055

Cited by 45 publications

(84 citation statements)

References 70 publications

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“…An inhibitory role of RhoB in endothelial barrier formation was also implicated in TNF‐simulated HUVEC and vascular endothelial cells in Crohn('s disease . Mechanistically, we found that RhoB was constitutively degraded in lysosomes, and the degradation process was mediated through K63 polyubiquitination at lysine 162 and 181 of RhoB by CUL3/KCTD10 …”

Section: Introductionmentioning

confidence: 69%

“…Interestingly, the translocation of Rac1 was inhibited by high expression of RhoB, resulting in impaired barrier restoration . Given our finding of the constitutive degradation of RhoB by CUL3/KCTD10, CUL3/KCTD10 may be critical for Rac1 trafficking and activation through RhoB degradation.…”

Section: Introductionmentioning

confidence: 71%

“…CUL3 also regulates endothelial functions (e.g. cell proliferation and barrier function) and angiogenesis by formation of complexes with multiple BTBP . Recently, we found that CUL3 or KCTD10, one of the BTBP, is essential for endothelial barrier functions in HUVEC .…”

Section: Introductionmentioning

confidence: 98%

“…cell proliferation and barrier function) and angiogenesis by formation of complexes with multiple BTBP . Recently, we found that CUL3 or KCTD10, one of the BTBP, is essential for endothelial barrier functions in HUVEC . Loss of CUL3 or KCTD10 induces strong actin polymerization and cell contraction, inhibiting the proper generation of endothelial barriers .…”

Section: Introductionmentioning

confidence: 99%

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Cullin‐3/KCTD10 E3 complex is essential for Rac1 activation through RhoB degradation in human epidermal growth factor receptor 2‐positive breast cancer cells

et al. 2019

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Rho GTPase Rac1 is a central regulator of F‐actin organization and signal transduction to control plasma membrane dynamics and cell proliferation. Dysregulated Rac1 activity is often observed in various cancers including breast cancer and is suggested to be critical for malignancy. Here, we showed that the ubiquitin E3 ligase complex Cullin‐3 (CUL3)/KCTD10 is essential for epidermal growth factor (EGF)‐induced/human epidermal growth factor receptor 2 (HER2)‐dependent Rac1 activation in HER2‐positive breast cancer cells. EGF‐induced dorsal membrane ruffle formation and cell proliferation that depends on both Rac1 and HER2 were suppressed in CUL3‐ or KCTD10‐depleted cells. Mechanistically, CUL3/KCTD10 ubiquitinated RhoB for degradation, another Rho GTPase that inhibits Rac1 activation at the plasma membrane by suppressing endosome‐to‐plasma membrane traffic of Rac1. In HER2‐positive breast cancers, high expression of Rac1 mRNA significantly correlated with poor prognosis of the patients. This study shows that this novel molecular axis (CUL3/KCTD10/RhoB) positively regulates the activity of Rac1 in HER2‐positive breast cancers, and our findings may lead to new treatment options for HER2‐ and Rac1‐positive breast cancers.

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Section: Introductionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cullin‐3/KCTD10 E3 complex is essential for Rac1 activation through RhoB degradation in human epidermal growth factor receptor 2‐positive breast cancer cells

et al. 2019

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“…In endothelial cells, RhoB half‐life is regulated by polyubiquitination at lysines 162 and 181 (Kovačević et al, ), therefore we generated BECs stably expressing Myc‐tagged RhoB K162R/K181R and assessed RhoB expression on soft substrates. Although RhoB K162R/K181R was generally expressed at lower levels than wild‐type even on plastic, seeding these cells on gels further reduced RhoB expression suggesting that ubiquitination was not required for RhoB downregulation (Figure b).…”

Section: Resultsmentioning

confidence: 99%

Matrix stiffness regulates endosomal escape of uropathogenicE. coli

Moorthy

Byfield

Janmey

et al. 2020

Cellular Microbiology

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Uropathogenic E. coli (UPEC) infection in vivo is characterized by invasion of bladder umbrella epithelial cells followed by endosomal escape and proliferation in the cytoplasm to form intracellular bacterial communities. By contrast, UPEC infection in tissue culture models results in bacteria being trapped within Lamp1‐positive endosomes where proliferation is limited. Pharmacological disruption of the actin cytoskeleton has been shown to facilitate UPEC endosomal escape in vitro and extracellular matrix stiffness is a well‐characterized physiological regulator of actin dynamics; therefore, we hypothesized that substrate stiffness may play a role in UPEC endosomal escape. Using functionalized polyacrylamide substrates, we found that at physiological stiffness, UPEC escaped the endosome and proliferated rapidly in the cytoplasm of bladder epithelial cells. Dissection of the cytoskeletal signaling pathway demonstrated that inhibition of the Rho GTPase RhoB or its effector PRK1 was sufficient to increase cytoplasmic bacterial growth and that RhoB protein level was significantly reduced at physiological stiffness. Our data suggest that tissue stiffness is a critical regulator of intracellular bacterial growth. Due to the ease of doing genetic and pharmacological manipulations in cell culture, this model system may provide a useful tool for performing mechanistic studies on the intracellular life cycle of uropathogens.

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KCTD10 Biology: An Adaptor for the Ubiquitin E3 Complex Meets Multiple Substrates

Maekawa

Higashiyama

2020

BioEssays

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Protein ubiquitination constitutes a post‐translational modification mediated by ubiquitin ligases whereby ubiquitinated substrates are degraded through the proteasomal or lysosomal pathways, or acquire novel molecular functions according to their “ubiquitin codes.” Dysfunction of the ubiquitination process in cells causes various diseases such as cancers along with neurodegenerative, auto‐immune/inflammatory, and metabolic diseases. KCTD10 functions as a substrate recognition receptor for cullin‐3 (CUL3), a scaffold protein in RING‐type ubiquitin ligase complexes. Recently, studies by ourselves and others have identified new substrates that are ubiquitinated by the CUL3/KCTD10 ubiquitin ligase complex. Moreover, the type of polyubiquitination (e.g., K27‐, K48‐, or K63‐chain) of various substrates (e.g., RhoB, CEP97, EIF3D, and TRIF) mediated by KCTD10 underlies its divergent roles in endothelial barrier formation, primary cilium formation, plasma membrane dynamics, cell proliferation, and immune response. Here, the physiological functions of KCTD10 are summarized and potential mechanisms are proposed.

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The Cullin-3–Rbx1–KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB

Cited by 45 publications

References 70 publications

Cullin‐3/KCTD10 E3 complex is essential for Rac1 activation through RhoB degradation in human epidermal growth factor receptor 2‐positive breast cancer cells

Cullin‐3/KCTD10 E3 complex is essential for Rac1 activation through RhoB degradation in human epidermal growth factor receptor 2‐positive breast cancer cells

Matrix stiffness regulates endosomal escape of uropathogenicE. coli

KCTD10 Biology: An Adaptor for the Ubiquitin E3 Complex Meets Multiple Substrates

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