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1.
Nat Commun ; 14(1): 7859, 2023 Nov 29.
Article in English | MEDLINE | ID: mdl-38030597

ABSTRACT

Ligand-induced epidermal growth factor receptor (EGFR) endocytosis followed by endosomal EGFR signaling and lysosomal degradation plays important roles in controlling multiple biological processes. ADP-ribosylation factor (Arf)-like protein 4 A (Arl4A) functions at the plasma membrane to mediate cytoskeletal remodeling and cell migration, whereas its localization at endosomal compartments remains functionally unknown. Here, we report that Arl4A attenuates EGFR degradation by binding to the endosomal sorting complex required for transport (ESCRT)-II component VPS36. Arl4A plays a role in prolonging the duration of EGFR ubiquitinylation and deterring endocytosed EGFR transport from endosomes to lysosomes under EGF stimulation. Mechanistically, the Arl4A-VPS36 direct interaction stabilizes VPS36 and ESCRT-III association, affecting subsequent recruitment of deubiquitinating-enzyme USP8 by CHMP2A. Impaired Arl4A-VPS36 interaction enhances EGFR degradation and clearance of EGFR ubiquitinylation. Together, we discover that Arl4A negatively regulates EGFR degradation by binding to VPS36 and attenuating ESCRT-mediated late endosomal EGFR sorting.


Subject(s)
Endosomal Sorting Complexes Required for Transport , ErbB Receptors , Humans , Endosomal Sorting Complexes Required for Transport/genetics , Endosomal Sorting Complexes Required for Transport/metabolism , HeLa Cells , ErbB Receptors/metabolism , Endosomes/metabolism , Signal Transduction , Protein Transport/physiology
2.
PLoS One ; 7(12): e52555, 2012.
Article in English | MEDLINE | ID: mdl-23285084

ABSTRACT

miRNA cluster miR-17-92 is known as oncomir-1 due to its potent oncogenic function. miR-17-92 is a polycistronic cluster that encodes 6 miRNAs, and can both facilitate and inhibit cell proliferation. Known targets of miRNAs encoded by this cluster are largely regulators of cell cycle progression and apoptosis. Here, we show that miRNAs encoded by this cluster and sharing the seed sequence of miR-17 exert their influence on one of the most essential cellular processes - endocytic trafficking. By mRNA expression analysis we identified that regulation of endocytic trafficking by miR-17 can potentially be achieved by targeting of a number of trafficking regulators. We have thoroughly validated TBC1D2/Armus, a GAP of Rab7 GTPase, as a novel target of miR-17. Our study reveals regulation of endocytic trafficking as a novel function of miR-17, which might act cooperatively with other functions of miR-17 and related miRNAs in health and disease.


Subject(s)
Endocytosis/genetics , GTPase-Activating Proteins/metabolism , MicroRNAs/metabolism , Base Sequence , Cell Proliferation , Down-Regulation/genetics , Epidermal Growth Factor/metabolism , GTPase-Activating Proteins/chemistry , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , HeLa Cells , Humans , MicroRNAs/genetics , Molecular Sequence Data , Protein Structure, Tertiary , Protein Transport/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, LDL/metabolism , Reproducibility of Results
3.
J Cell Sci ; 124(Pt 23): 4014-26, 2011 Dec 01.
Article in English | MEDLINE | ID: mdl-22159419

ABSTRACT

ADP-ribosylation factor-like protein 4A (ARL4A) is a developmentally regulated member of the ARF/ARL GTPase family. The primary structure of ARL4A is very similar to that of other ARF/ARL molecules, but its function remains unclear. The trans-Golgi network golgin GCC185 is required for maintenance of Golgi structure and distinct endosome-to-Golgi transport. We show here that GCC185 acts as a new effector for ARL4 to modulate Golgi organization. ARL4A directly interacts with GCC185 in a GTP-dependent manner. Sub-coiled-coil regions of the CC2 domain of GCC185 are required for the interaction between GCC185 and ARL4A. Depletion of ARL4A reproduces the GCC185-depleted phenotype, causing fragmentation of the Golgi compartment and defects in endosome-to-Golgi transport. GCC185 and ARL4A localize to the Golgi independently of each other. Deletion of the ARL4A-interacting region of GCC185 results in inability to maintain Golgi structure. Depletion of ARL4A impairs the interaction between GCC185 and cytoplasmic linker-associated proteins 1 and 2 (CLASP1 and CLASP2, hereafter CLASPs) in vivo, and abolishes the GCC185-mediated Golgi recruitment of these CLASPs, which is crucial for the maintenance of Golgi structure. In summary, we suggest that ARL4A alters the integrity of the Golgi structure by facilitating the interaction of GCC185 with CLASPs.


Subject(s)
ADP-Ribosylation Factors/metabolism , Golgi Apparatus/physiology , Membrane Proteins/metabolism , Amino Acid Sequence , Endosomes/metabolism , Golgi Apparatus/metabolism , Golgi Matrix Proteins , HEK293 Cells , HeLa Cells , Humans , Immunoprecipitation , Microtubule-Associated Proteins/metabolism , Protein Interaction Domains and Motifs , Protein Transport , Sequence Deletion , Substrate Specificity , Transfection , Two-Hybrid System Techniques
4.
J Cell Sci ; 123(Pt 20): 3478-89, 2010 Oct 15.
Article in English | MEDLINE | ID: mdl-20841378

ABSTRACT

In yeast, Arl3p recruits Arl1p GTPase to regulate Golgi function and structure. However, the molecular mechanism involved in regulating activation of Arl1p at the Golgi is unknown. Here, we show that Syt1p promoted activation of Arl1p and recruitment of a golgin protein, Imh1p, to the Golgi. Deletion of SYT1 resulted in the majority of Arl1p being distributed diffusely throughout the cytosol. Overexpression of Syt1p increased Arl1p-GTP production in vivo and the Syt1-Sec7 domain promoted nucleotide exchange on Arl1p in vitro. Syt1p function required the N-terminal region, Sec7 and PH domains. Arl1p, but not Arl3p, interacted with Syt1p. Localization of Syt1p to the Golgi did not require Arl3p. Unlike arl1Δ or arl3Δ mutants, syt1Δ did not show defects in Gas1p transport, cell wall integrity or vacuolar structure. These findings reveal that activation of Arl1p is regulated in part by Syt1p, and imply that Arl1p activation, by using more than one GEF, exerts distinct biological activities at the Golgi compartment.


Subject(s)
Golgi Apparatus/metabolism , Guanine Nucleotide Exchange Factors/metabolism , Monomeric GTP-Binding Proteins/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/metabolism , Vesicular Transport Proteins/metabolism , Biological Transport/genetics , Biological Transport/physiology , Cell Wall/genetics , Cell Wall/metabolism , Electrophoresis, Polyacrylamide Gel , Fluorescent Antibody Technique, Indirect , Guanine Nucleotide Exchange Factors/genetics , Membrane Glycoproteins/metabolism , Monomeric GTP-Binding Proteins/genetics , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics , Two-Hybrid System Techniques , Vesicular Transport Proteins/genetics
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