Review
ARF6-mediated endocytic recycling impacts cell movement, cell division and lipid homeostasis

https://doi.org/10.1016/j.semcdb.2010.09.002Get rights and content

Abstract

A wide range of cellular activities depends upon endocytic recycling. ARF6, a small molecular weight GTPase, regulates the processes of endocytosis and endocytic recycling in concert with various effector molecules and other small GTPases. This review highlights three critical processes that involve ARF6-mediated endosomal membrane trafficking—cell motility, cytokinesis, and cholesterol homeostasis. In each case, the function of ARF6-mediated trafficking varies—including localization of specific protein and lipid cargo, regulation of bulk membrane movement, and modulation of intracellular signaling. As described in this review, mis-regulation of endocytic traffic can result in human disease when it compromises the cell's ability to regulate cell movement and invasion, cell division, and lipid homeostasis.

Introduction

ARF6 is a small molecular weight GTPase that localizes to the plasma membrane and endosomal compartments where it regulates endocytic membrane trafficking and actin remodeling (reviewed in [1]). Like other small GTPases, ARF6 cycles between its active-GTP-bound and inactive-GDP-bound conformations. Guanine nucleotide exchange factors, GEFs, activate ARF6 by mediating exchange of GTP for GDP, whereas GTPase-activating proteins, GAPs, downregulate ARF6 activity through hydrolysis of GTP to GDP. As ARF6 cycles through its active and inactive conformations it facilitates ligand internalization at the cell surface, further trafficking along the endocytic pathway following internalization, and endosomal recycling and subsequent fusion of an endosomal membrane with the plasma membrane. Distinct effector molecules determine the result of ARF6 GTP/GDP cycling at discrete subcellular locations. At the cell surface ARF6-GTP can facilitate ligand internalization, whereas activation of ARF6 is also required for recycling of membrane back to the cell surface [1]. Recycling to the plasma membrane can occur directly from the sorting endosome, “fast” recycling, or through a pericentriolar endosomal recycling compartment (ERC), “slow” recycling. The longer-lived ERC seems to consist of a heterogeneous subset of endosomal populations, which may vary among cell types [1], [2]. This review focuses on processes involving ARF6-mediated endosomal membrane trafficking.

The family of Rab GTPases also regulates intracellular vesicular trafficking, with distinct Rabs operating at various stages along the endocytic pathway [3]. Rab4, an early endosomal Rab, localizes to sorting endosomes and mediates “fast” endosomal recycling [2]. Some Rabs, namely Rab11 and Rab8, often functionally overlap with ARF6 in mediating endosomal recycling required for the cellular processes described in this review. Rab11 is a resident protein of the ERC and regulates transport from this compartment to various locations, including both the TGN and the plasma membrane. When Rab11 function is perturbed, exit out of the ERC is blocked [2]. Recently, a family of effector molecules, known as arfophilins or FIPs, have been shown to bind to both ARF6 and Rab11 and are involved in some trafficking events mediated by these GTPases [4], [5]. The function of Rab8 has been more difficult to identify. In polarized cells, Rab8 appears to mediate the transport of newly synthesized proteins en route from the Golgi to the plasma membrane, using recycling endosomes as an intermediate [6], [7]. Recent work in non-polarized cells indicates that Rab8 can regulate the trafficking of newly endocytosed ligands and that Rab8 and ARF6 may sometimes function in a common endocytic recycling pathway [8].

A wide range of cellular activities depends upon endocytic recycling. This review focuses on the ways by which endosomal trafficking directed by ARF6 and other small GTPases impacts cell motility, cell division, and cholesterol homeostasis (Table 1). During cell migration and invasion, ARF6-regulated endosomal traffic promotes loss of cell–cell contacts, changes in cell shape, and proteolysis of extracellular matrix. During cytokinesis, endosomal recycling mediated by ARF6 is required for the completion of abscission. In the regulation of cholesterol homeostasis, endosomal recycling facilitates normal cholesterol efflux and can alleviate aberrant cholesterol accumulation. In each case, the function of ARF6-mediated trafficking varies—including localization of specific protein and lipid cargo, regulation of bulk membrane movement, and modulation of intracellular signaling. As described in this review, mis-regulation of endocytic traffic can result in human disease when it compromises the cell's ability to regulate cell movement and invasion, cell division, and lipid homeostasis.

Section snippets

ARF6 regulates epithelial cell–cell adhesion

ARF6-directed trafficking regulates multiple events that impinge upon cell migration and tumor cell invasion. These processes include endocytic membrane recycling, trafficking and targeting of adhesion molecules and proteases, and rearrangements of the actin cytoskeleton. Modulation of ARF6 activity influences the cell's ability to perform these processes, and thus directly impacts migratory and invasive capacity.

It has been demonstrated that ARF6 regulates the internalization and trafficking

Abscission requires endocytic recycling

As the final step of mitosis, cytokinesis completes cell division and produces two new daughter cells. During telophase the formation and action of the actomyosin contractile ring begins to divide the elongating cell into two daughter cells and the plasma membrane ingresses at a region called the cleavage furrow. After the cleavage furrow ingresses, forming a deep invagination, the two new daughter cells remain connected by a thin intercellular bridge. At the center of the intercellular bridge

ARF6-regulated endosomal recycling alleviates NPC1 disease phenotype

Cholesterol homeostasis relies on multiple feedback mechanisms that sense cholesterol levels and modulate uptake or efflux accordingly. Vesicular trafficking impacts the fate of cholesterol within the cell [88]. Previous work has shown that cholesterol traffics through the ARF6-regulated endosomal pathway [89]. The functional importance of maintaining cholesterol homeostasis is manifested by the variety of disorders, including neurodegenerative and cardiovascular diseases, which result when

Conclusion

Here we have highlighted the ways by which ARF6-directed membrane trafficking allows cells to become migratory and invade extracellular matrix, to complete the process of cytokinesis, and to modulate intracellular cholesterol levels. Although we focused our discussion on vesicular trafficking, the effects of ARF6 action are not limited to membrane traffic. Certainly, its ability to induce cortical actin rearrangements impacts cell migration and invasion as well as other cellular activities. The

Acknowledgements

We apologize to those investigators whose work was not cited or indirectly cited, due to space constraints. We thank Christine Monteleon for critical reading of the manuscript. Research in the D'Souza-Schorey Laboratory on the topics described here has been supported in part by the American Cancer Society, the National Cancer Institute, the Leukemia and Lymphoma Society of America, the Walther Foundation and the Leda J. Sears Trust.

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