Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity

Christopher A. Jones; Naoyuki Nishiya; Nyall R. London; Weiquan Zhu; Lise K. Sorensen; Aubrey C. Chan; Chinten J. Lim; Haoyu Chen; Qisheng Zhang; Peter G. Schultz; Alaa M. Hayallah; Kirk R. Thomas; Michael Famulok; Kang Zhang; Mark H. Ginsberg; Dean Y. Li

doi:10.1038/ncb1976

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Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity

Journal article

Peer reviewed

Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity

Christopher A. Jones, Naoyuki Nishiya, Nyall R. London, Weiquan Zhu, Lise K. Sorensen, Aubrey C. Chan, Chinten J. Lim, Haoyu Chen, Qisheng Zhang, Peter G. Schultz, …

Nature cell biology, Vol.11(11), pp.1325-U146

11/01/2009

DOI: 10.1038/ncb1976

PMCID: PMC2854659

PMID: 19855388

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https://www.ncbi.nlm.nih.gov/pmc/articles/2854659View

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Abstract

Slit-Roundabout (Robo) signalling has a well-understood role in axon guidance(1-5). Unlike in the nervous system, however, Slit-dependent activation of an endothelial-specific Robo, Robo4, does not initiate a guidance program. Instead, Robo4 maintains the barrier function of the mature vascular network by inhibiting neovascular tuft formation and endothelial hyperpermeability induced by pro-angiogenic factors(6). In this study, we used cell biological and biochemical techniques to elucidate the molecular mechanism underlying the maintenance of vascular stability by Robo4. Here, we demonstrate that Robo4 mediates Slit2-dependent suppression of cellular protrusive activity through direct interaction with the intracellular adaptor protein paxillin and its paralogue, Hic-5. Formation of a Robo4-paxillin complex at the cell surface blocks activation of the small GTPase Arf6 and, consequently, Rac by recruitment of Arf-GAPs (ADP-ribosylation factor-directed GTPase-activating proteins) such as GIT1. Consistent with these in vitro studies, inhibition of Arf6 activity in vivo phenocopies Robo4 activation by reducing pathologic angiogenesis in choroidal and retinal vascular disease and VEGF-165 (vascular endothelial growth factor-165)-induced retinal hyperpermeability. These data reveal that a Slit2-Robo4-paxillin-GIT1 network inhibits the cellular protrusive activity underlying neovascularization and vascular leak, and identify a new therapeutic target for ameliorating diseases involving the vascular system.

Cell Biology

Life Sciences & Biomedicine

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Title: Subtitle: Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity
Creators: Christopher A. Jones - University of Utah
Naoyuki Nishiya - Iwate Medical University
Nyall R. London - University of Utah
Weiquan Zhu - University of Utah
Lise K. Sorensen - University of Utah
Aubrey C. Chan - University of Utah
Chinten J. Lim - University of California San Diego
Haoyu Chen - Shantou University
Qisheng Zhang - University of North Carolina at Chapel Hill
Peter G. Schultz - Scripps Research Institute
Alaa M. Hayallah - Assiut University
Kirk R. Thomas - University of Utah
Michael Famulok - University of Bonn
Kang Zhang - University of California San Diego
Mark H. Ginsberg - University of California San Diego
Dean Y. Li - University of Utah
Resource Type: Journal article
Publication Details: Nature cell biology, Vol.11(11), pp.1325-U146
DOI: 10.1038/ncb1976
PMID: 19855388
PMCID: PMC2854659
NLM abbreviation: Nat Cell Biol
ISSN: 1465-7392
eISSN: 1476-4679
Publisher: Springer Nature
Number of pages: 21
Grant note: T32GM007464 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) SFB 704 / Deutsche Forschungsgemeinschaft; German Research Foundation (DFG) R01HL077671 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) H. A. and Edna Benning Foundation, the Juvenile Diabetes Research Foundation, the American Heart Association, the Burroughs Wellcome Fund and the Department of Defense; American Heart Association; Juvenile Diabetes Research Foundation National Heart Lung and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) U54AI065357 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) National Eye Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Eye Institute (NEI) National Institute of Arthritis and Musculoskeletal and Skin Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) AI065357 / National Institute of Allergy and Disease; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) T32-GM007464 / US National Institutes of Health, Ruth L. Kirschstein National Research Service Award; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
Language: English
Date published: 11/01/2009
Academic Unit: Psychiatry; Internal Medicine
Record Identifier: 9984280876802771

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