Arf and Rho GAP adapter protein ARAP1 participates in the mobilization of TRAIL-R1/DR4 to the plasma membrane
Language English Country Netherlands Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Apoptosis drug effects MeSH
- Cell Membrane metabolism MeSH
- Cell Line MeSH
- Down-Regulation MeSH
- Humans MeSH
- RNA, Small Interfering pharmacology MeSH
- Protein Interaction Mapping MeSH
- Cell Line, Tumor MeSH
- TNF-Related Apoptosis-Inducing Ligand metabolism MeSH
- GTPase-Activating Proteins physiology MeSH
- Receptors, Tumor Necrosis Factor metabolism MeSH
- Two-Hybrid System Techniques MeSH
- Receptors, TNF-Related Apoptosis-Inducing Ligand MeSH
- Protein Transport physiology MeSH
- Carrier Proteins physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- ARAP1 protein, human MeSH Browser
- RNA, Small Interfering MeSH
- TNF-Related Apoptosis-Inducing Ligand MeSH
- GTPase-Activating Proteins MeSH
- Receptors, Tumor Necrosis Factor MeSH
- TNFRSF10A protein, human MeSH Browser
- TNFSF10 protein, human MeSH Browser
- Receptors, TNF-Related Apoptosis-Inducing Ligand MeSH
- Carrier Proteins MeSH
TRAIL, a ligand of the TNFalpha family, induces upon binding to its pro-death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5 the apoptosis of cancer cells. Activated receptors incite the formation of the Death-Inducing Signaling Complex followed by the activation of the downstream apoptotic signaling. TRAIL-induced apoptosis is regulated at multiple levels, one of them being the presence and relative number of TRAIL pro- and anti-apoptotic receptors on the cytoplasmic membrane. In a yeast two-hybrid search for proteins that interact with the intracellular part (ICP) of DR4, we picked ARAP1, an adapter protein with ArfGAP and RhoGAP activities. In yeast, DR4(ICP) interacts with the alternatively spliced ARAP1 lacking 11 amino acids from the PH5 domain. Transfected ARAP1 co-precipitates with DR4 and co-localizes with it in the endoplasmic reticulum/Golgi, at the cytoplasmic membrane and in early endosomes of TRAIL-treated cells. ARAP1 knockdown significantly compromises the localization of DR4 at the cell surface of several tumor cell lines and slows down their TRAIL-induced death. ARAP1 overexpressed in HEL cells does not affect their TRAIL-induced apoptosis or the membrane localization of DR4, but it enhances the cell-surface presentation of phosphatidyl serine. Our data indicate that ARAP1 is likely involved in the regulation of the cell-specific trafficking of DR4 and might thus affect the efficacy of TRAIL-induced apoptosis.
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