期刊
JOURNAL OF CELL BIOLOGY
卷 183, 期 3, 页码 499-511出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200806016
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资金
- Wellcome [GR077544AIA]
- Medical Research Council [G0300452]
- Biotechnology and Biological Sciences Research Council [BBS/B/04072]
- British Heart Foundation [FS/2001053]
- National Institutes of Health [GM67237]
- Cancer Research UK
- MRC [G0300452] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/B/04072] Funding Source: researchfish
- Medical Research Council [G0300452] Funding Source: researchfish
Here we investigate the role of rab5 and its cognate exchange factors rabex-5 and hRME-6 in the regulation of AP2 uncoating from endocytic clathrin-coated vesicles (CCVs). In vitro, we show that the rate of AP2 uncoating from CCVs is dependent on the level of functional rab5. In vivo, overexpression of dominant-negative rab5(S34N), or small interfering RNA (siRNA) mediated depletion of hRME-6, but not rabex-5, resulted in increased steady-state levels of AP2 associated with endocytic vesicles, which is consistent with reduced uncoating efficiency. hRME-6 guanine nucleotide exchange factor activity requires hRME-6 binding to alpha-adaptin ear, which displaces the ear-associated mu 2 kinase AAK1. siRNA-mediated depletion of hRME-6 increases phospho-mu 2 levels, and expression of a phosphomimetic mu 2 mutant increases levels of endocytic vesicle-associated AP2. Depletion of hRME-6 or rab5(S35N) expression also increases the levels of phosphoinositide 4,5-bisphosphate (PtdIns(4,5) P 2) associated with endocytic vesicles. These data are consistent with a model in which hRME-6 and rab5 regulate AP2 uncoating in vivo by coordinately regulating mu 2 dephosphorylation and PtdIns(4,5) P 2 levels in CCVs.
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