CXCR4 Stimulates Macropinocytosis: Implications for Cellular Uptake of Arginine-Rich Cell-Penetrating Peptides and HIV

Tanaka, Gen; Nakase, Ikuhiko; Fukuda, Yasunori; Masuda, Ryo; Oishi, Shinya; Shimura, Kazuya; Kawaguchi, Yusuke; Takatani‐Nakase, Tomoka; Langel, Ülo; Gräslund, Astrid; Okawa, Katsuya; Matsuoka, Masao; Fujii, Nobutaka; Hatanaka, Y.; Futaki, Shiroh

doi:10.1016/j.chembiol.2012.09.011

Cited by 103 publications

(106 citation statements)

References 48 publications

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“…5). Hep3B cells were resistant to the action of these inhibitors and CXCR4 internalization was blocked by DMA, an inhibitor of macropinocytosis [37] that specifically blocks SDF-1α induced internalization of CXCR4 (Fig. 6), but not other membrane receptors (Suppl.…”

Section: Discussionmentioning

confidence: 98%

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Mechanisms regulating cell membrane localization of the chemokine receptor CXCR4 in human hepatocarcinoma cells

Cepeda

Dediulia

Fernando

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Hepatocellular carcinoma (HCC) cells with a mesenchymal phenotype show an asymmetric subcellular distribution of the chemokine receptor CXCR4, which is required for cell migration and invasion. In this work we examine the mechanisms that regulate the intracellular trafficking of CXCR4 in HCC cells. Results indicate that HCC cells present CXCR4 at the cell surface, but most of this protein is in endomembranes colocalizing with markers of the Golgi apparatus and recycling endosomes. The presence of high protein levels of CXCR4 present at the cell surface correlates with a mesenchymal-like phenotype and a high autocrine activation of the Transforming Growth Factor-beta (TGF-β) pathway. CXCR4 traffics along the Golgi/exocyst/plasma membrane pathway and requires EXOC4 (Sec8) component of the exocyst complex. HCC cells use distinct mechanisms for the CXCR4 internalization such as dynamin-dependent endocytosis and macropinocytosis. Regardless of the endocytic mechanisms, colocalization of CXCR4 and Rab11 is observed, which could be involved not only in receptor recycling but also in its post-Golgi transport. In summary, this work highlights membrane trafficking pathways whose pharmacological targeting could subsequently result in the inactivation of one of the main guiding mechanisms used by metastatic cells to colonize secondary organs and tissues.

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Section: Discussionmentioning

confidence: 98%

“…It has been recently reported that CXCR4 could also be internalized by macropinocytosis. Therefore, we treated Hep3B cells with dimethylamiloride (DMA), which is an inhibitor of this internalization pathway [37]. As shown in Fig.…”

Section: Sdf-1α Induces the Internalization Of Cxcr4mentioning

confidence: 99%

Mechanisms regulating cell membrane localization of the chemokine receptor CXCR4 in human hepatocarcinoma cells

Cepeda

Dediulia

Fernando

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Endocytosis is a generic term for several different processes, such as phagocytosis for large particles and pinocytosis for smaller ones, as well as receptor-mediated endocytosis in which clathrin or caveolin pits are involved (Madani et al, 2011). Several receptors were uncovered to be involved in internalization of CPPs, such as chemokine receptors (Tanaka et al, 2012), syndecans (Letoha et al, 2010), neuropilins (Prud'homme and Glinka, 2012), the family of integrins (Mokhtarieh et al, 2013), homing sequences, and positively-charged scavenger receptors (Reissmann, 2014). Micropinocytosis appears to be a pathway for the MCoTI-II peptide to enter into the cell.…”

Section: Translocation Of Cpps Into Cellsmentioning

confidence: 99%

Viral and Other Cell-Penetrating Peptides as Vectors of Therapeutic Agents in Medicine

Durzyńska

Przysiecka

Nawrot

et al. 2015

J Pharmacol Exp Ther

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Efficient delivery of heterologous molecules for treatment of cells is a great challenge in modern medicine and pharmacology. Cellpenetrating peptides (CPPs) may improve efficient delivery of a wide range of macromolecular cargos, including plasmid DNA, small interfering RNA, drugs, nanoparticulate pharmaceutical carriers, and anticancer drugs. In this paper, we present the history of CPPs' discovery with special attention drawn to sequences of viral origin. We also describe different CPP families with regard to their physicochemical properties and numerous mechanisms of CPP cell uptake by direct penetration and endocytotic pathways. A detailed description is focused on formation of carrier-cargo complexes, which are needed for practical use of CPPs in medicine and biotechnology. Examples of successful application of CPPs in treatment of human diseases are also presented, including decreased tumor growth and induction of cancer cell death. Finally, we review modern design approaches to novel CPPs and prediction of their activity. To sum up, the current review presents a thorough and up-to-date knowledge of CPPs and may be a valuable source of information for researchers in pharmacology designing new therapeutic agents.

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“…15) Furthermore, a membrane-associated chemokine receptor CXCR4 is proposed to serve as a cell-surface receptor responsible for internalization of dodeca-arginine (R12) via macropinocytosis. 16) On the other hand, there is also strong evidence that other classes of endocytosis pathways such as clathrin-mediated endocytosis [17][18][19] and caveolae-mediated endocytosis 20,21) are involved in internalization of these peptides. It is noted that internalization modes of arginine-rich CPPs can be strongly affected by variable factors in each experiment, such as the physicochemical natures of peptides, cell types, incubation temperatures and cargoes to be delivered, which makes mechanistic studies on their internalization exceptionally difficult.…”

Section: Introductionmentioning

confidence: 99%

Current Understanding of Direct Translocation of Arginine-Rich Cell-Penetrating Peptides and Its Internalization Mechanisms

2016

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Arginine-rich cell-penetrating peptides (CPPs) including Tat, Penetratin and oligoarginine peptides are a series of short peptides that can be efficiently internalized into cells and have been widely used as carriers for intracellular delivery of bioactive molecules. In the early phase of the study, CPPs, as well as their conjugates, were thought to rapidly enter cells by direct penetration through membranes, which was later found to be an experimental artifact that was concluded from observations in fixed cells. Although re-evaluation using living unfixed cells revealed that endocytosis has a major role in internalization of these peptides, there are a number of studies reporting that, even if fixation is avoided, direct translocation across plasma membranes and cytosolic distribution of arginine-rich CPPs are still observed in cells without membrane perturbation. In addition, amphiphilic counteranions such as pyrenebutyrate dramatically accelerate direct translocation of these peptides into cells. These results suggest that there are at least two pathways, i.e., endocytosis and direct translocation, both of which would contribute to cellular internalization of arginine-rich CPPs. In this review, we first introduce the story of fixation artifact, which indeed led to the critical progress in CPP study, and then summarize the current understanding for direct translocation of arginine-rich CPPs. Comprehensive understanding of direct translocation of these peptides and its mechanistic elucidation would provide useful knowledge for developing methodologies that would enable efficient intracellular delivery.

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CXCR4 Stimulates Macropinocytosis: Implications for Cellular Uptake of Arginine-Rich Cell-Penetrating Peptides and HIV

Cited by 103 publications

References 48 publications

Mechanisms regulating cell membrane localization of the chemokine receptor CXCR4 in human hepatocarcinoma cells

Mechanisms regulating cell membrane localization of the chemokine receptor CXCR4 in human hepatocarcinoma cells

Viral and Other Cell-Penetrating Peptides as Vectors of Therapeutic Agents in Medicine

Current Understanding of Direct Translocation of Arginine-Rich Cell-Penetrating Peptides and Its Internalization Mechanisms

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