Rabex-5 Protein Regulates the Endocytic Trafficking Pathway of Ubiquitinated Neural Cell Adhesion Molecule L1

Aikawa, Yoshikatsu

doi:10.1074/jbc.m112.374322

Cited by 13 publications

(40 citation statements)

References 48 publications

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“…Rabex-5, EHD1/4, EEA1) have been implied in L1 surface recycling (Aikawa, 2012;Yap et al, 2010;Lasiecka et al, 2014). For example, the surface expression of L1 is increased in dendrites of EHD1-overexpressing neurons (Yap et al, 2010).…”

Section: Sara Regulates the Surface Expression Of L1mentioning

confidence: 99%

SARA regulates neuronal migration during neocortical development through L1 trafficking

et al. 2016

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Emerging evidence suggests that endocytic trafficking of adhesion proteins plays a crucial role in neuronal migration during neocortical development. However, molecular insights into these processes remain elusive. Here, we study the early endosomal protein Smad anchor for receptor activation (SARA) in the developing mouse brain. SARA is enriched at the apical endfeet of radial glia of the neocortex. Although SARA knockdown did not lead to detectable neurogenic phenotypes, SARA-suppressed neurons exhibited impaired orientation and migration across the intermediate zone. Mechanistically, we show that SARA knockdown neurons exhibit increased surface expression of the L1 cell adhesion molecule. Neurons ectopically expressing L1 phenocopy the migration and orientation defects caused by SARA knockdown and display increased contact with neighboring neurites. L1 knockdown effectively rescues SARA suppressioninduced phenotypes. SARA knockdown neurons eventually overcome their migration defect and enter later into the cortical plate. Nevertheless, these neurons localize at more superficial cortical layers than their control counterparts. These results suggest that SARA regulates the orientation, multipolar-to-bipolar transition and the positioning of cortical neurons via modulating surface L1 expression.

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Section: Sara Regulates the Surface Expression Of L1mentioning

confidence: 99%

SARA regulates neuronal migration during neocortical development through L1 trafficking

et al. 2016

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“…To exert Ub-ligase activity, the A20-ZnF domain binds Ub-charged Ubc5 (an E2 enzyme) in a manner that depends upon the residues involved in Ub binding. In a previous study, we reported that the MIU domain, rather than the A20-ZnF domain, is specifically involved in the trafficking of ubiquitinated cargo into endosomes via a direct interaction (18). Our findings thus suggested that the MIU and A20-ZnF domains are functionally distinct in the Ub signaling pathways.…”

mentioning

confidence: 76%

“…Cell Culture, Transfection, and DNA Constructs-Mouse neuroblastoma N2a cells and human embryonic kidney 293T (HEK293T) cells were cultured and transfected by using Lipofectamine 2000 (Invitrogen) as described previously (18). The human Rab5a construct was amplified using PCR from cDNA and subcloned into an EGFP-N1 vector.…”

Section: Methodsmentioning

confidence: 99%

“…The recruitment of the Rabaptin5⅐Rabex-5 complex to early endosomal membranes containing Rab5-GTP has been proposed as a positive-feedback mechanism that results in the local nucleotide exchange of Rab5 in restricted areas of the endosomal membrane (19,23). Rabex-5 has been reported to get translocated to the plasma membrane upon ligand stimulation with either the EGF or L1 antibody (Ab) (14,18) and induce the production of Rab5-positive enlarged vacuoles due to the increment of the activated form of Rab5 (18). These findings suggest a plausible mechanism of ubiquitinated cargo trafficking, which is similar to that of the vacuolar protein sorting 9 protein (Vps9p), a yeast homolog of Rabex-5, wherein cross-talk occurs between the GEF activity of the VPS9 domain, and the Ub-binding activity, which involves the coupling of Ub conjugation to the ER degradation (CUE) domain (24).…”

mentioning

confidence: 99%

“…To investigate the molecular mechanism that integrates the Ub-binding and GEF activities of Rabex-5, we employed the Rabex-5-mediated endocytic pathway of the ubiquitinated neuronal cell adhesion molecule L1 as the model system (18) and assessed the functional impact of UBDs on GEF activity and vice versa. We found that Ub binding-deficient Rabex-5 mutants significantly diminish the interaction with Rab5.…”

mentioning

confidence: 99%

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Spatiotemporal Regulation of the Ubiquitinated Cargo-binding Activity of Rabex-5 in the Endocytic Pathway

Aikawa

Hirakawa

Lee

2012

Journal of Biological Chemistry

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Background:The regulatory mechanism underlying the interaction of the Rabex-5 MIU domain with ubiquitinated cargos remains unclear. Results: Rabex-5 guanine nucleotide exchange factor (GEF) mutants affected interactions of ubiquitinated cargos. Conclusion: GDP/GTP exchange in the GEF domain controls the MIU domain interactions with the ubiquitinated cargos. Significance: Rabex-5 GEF activity acts as an intramolecular switch for spatiotemporal trafficking of the ubiquitinated cargos.

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Integrin alpha v beta 6 contributes to maintaining corneal epithelial barrier function

Guo

Wang

et al. 2013

Cell Biology International

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The corneal epithelial barrier dysfunction is associated with a number of disorders of the cornea. This study aims to investigate the role of integrin alpha v beta 6 (avb6) in maintaining the corneal epithelial barrier function. In this study, the association of avb6 and endosome/lysosome in the human corneal epithelial cell line, HCE cells, was observed with immunocytochemistry. The corneal epithelial barrier function was assessed with HCE monolayers in Transwells. The results showed that avb6 was observed attaching to endosomes in HCE cells. Knockdown of avb6 resulted in disturbing the fusion of endosome/lysosome. Tumor necrosis factor (TNF)-α could bind avb6 to form a complex that interfered with the fusion of endosome/lysosome in HCE cells. With the HCE monolayer as a corneal epithelial barrier model, the knockdown of avb6 or exposure to TNF-α markedly increased the epithelial barrier permeability to a macomolecular protein, ovalbumin, in Transwell system. After passing through the deficient epithelial barrier, the ovalbumin molecules still conserved the antigenicity. We conclude that the integrin avb6 plays an important role in the fusion of endosome/lysosome in corneal epithelial cells; inhibition of avb6 results in corneal epithelial barrier dysfunction.

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Rabex-5 Protein Regulates the Endocytic Trafficking Pathway of Ubiquitinated Neural Cell Adhesion Molecule L1

Cited by 13 publications

References 48 publications

SARA regulates neuronal migration during neocortical development through L1 trafficking

SARA regulates neuronal migration during neocortical development through L1 trafficking

Spatiotemporal Regulation of the Ubiquitinated Cargo-binding Activity of Rabex-5 in the Endocytic Pathway

Integrin alpha v beta 6 contributes to maintaining corneal epithelial barrier function

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