1. Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy
- Author
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Zhu, Weiquan, Shi, Dallas S., Winter, Jacob M., Rich, Bianca E., Tong, Zongzhong, Sorensen, Lise K., Zhao, Helong, Huang, Yi, Tai, Zhengfu, Mleynek, Tara M., Yoo, Jae Hyuk, Dunn, Christine, Ling, Jing, Richards, Jackson R. Bergquist, Jake A., Jiang, Amanda, Lesniewski, Lisa A., Ward, M. Elizabeth Hartnet Diane M., Mueller, Alan L., Ostanin, Kirill, Thomas, Kirk R., Odelberg, Shannon J., and Li, Dean Y.
- Subjects
Diabetic retinopathy -- Genetic aspects -- Research ,Vascular endothelial growth factor -- Research ,Binding proteins -- Research ,Cellular signal transduction -- Research ,Health care industry - 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., Introduction Over 25 million people in the United States have diabetes mellitus (1) and are prone to suffer from its devastating sequelae. The metabolic derangements seen in diabetes lead to [...]
- Published
- 2017
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