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Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy
Weiquan Zhu, … , Shannon J. Odelberg, Dean Y. Li
Weiquan Zhu, … , Shannon J. Odelberg, Dean Y. Li
Published October 23, 2017
Citation Information: J Clin Invest. 2017;127(12):4569-4582. https://doi.org/10.1172/JCI91770.
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Research Article Cell biology Ophthalmology

Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy

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Abstract

The devastating sequelae of diabetes mellitus include microvascular permeability, which results in retinopathy. Despite clinical and scientific advances, there remains a need for new approaches to treat retinopathy. Here, we have presented a possible treatment strategy, whereby targeting the small GTPase ARF6 alters VEGFR2 trafficking and reverses signs of pathology in 4 animal models that represent features of diabetic retinopathy and in a fifth model of ocular pathological angiogenesis. Specifically, we determined that the same signaling pathway utilizes distinct GEFs to sequentially activate ARF6, and these GEFs exert distinct but complementary effects on VEGFR2 trafficking and signal transduction. ARF6 activation was independently regulated by 2 different ARF GEFs — ARNO and GEP100. Interaction between VEGFR2 and ARNO activated ARF6 and stimulated VEGFR2 internalization, whereas a VEGFR2 interaction with GEP100 activated ARF6 to promote VEGFR2 recycling via coreceptor binding. Intervening in either pathway inhibited VEGFR2 signal output. Finally, using a combination of in vitro, cellular, genetic, and pharmacologic techniques, we demonstrated that ARF6 is pivotal in VEGFR2 trafficking and that targeting ARF6-mediated VEGFR2 trafficking has potential as a therapeutic approach for retinal vascular diseases such as diabetic retinopathy.

Authors

Weiquan Zhu, Dallas S. Shi, Jacob M. Winter, Bianca E. Rich, Zongzhong Tong, Lise K. Sorensen, Helong Zhao, Yi Huang, Zhengfu Tai, Tara M. Mleynek, Jae Hyuk Yoo, Christine Dunn, Jing Ling, Jake A. Bergquist, Jackson R. Richards, Amanda Jiang, Lisa A. Lesniewski, M. Elizabeth Hartnett, Diane M. Ward, Alan L. Mueller, Kirill Ostanin, Kirk R. Thomas, Shannon J. Odelberg, Dean Y. Li

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Figure 8

Schematic depicting the function of ARF6 and its GEFs in VEGFR2 trafficking and signaling.

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Schematic depicting the function of ARF6 and its GEFs in VEGFR2 traffick...
VEGF stimulation induces VEGFR2 dimerization and phosphorylation as well as ARF6 activation. The effect of ARF6 on this pathway is specified by the particular GEF that activates it. GEP100-dependent ARF6 activity promotes VEGFR2 binding to its coreceptor NRP1 at the cell surface, while ARNO-dependent ARF6 activity promotes VEGFR2 internalization. When bound to NRP1, VEGFR2 exhibits decreased lysosomal localization and degradation and increased plasma membrane recycling. Thus, ARF6 mediates VEGFR2 internalization and coreceptor binding, 2 trafficking mechanisms that are necessary for maximal VEGFR2 phosphorylation and downstream signaling. Note: phosphorylation at Y1175 has been shown to increase upon internalization of VEGFR2 (41). For simplicity, we illustrate this increase by showing only 1 of the 2 VEGFR2 chains phosphorylated at the plasma membrane. However, the true phosphorylation state of each chain at the plasma membrane has not yet been elucidated.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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