Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity

Christopher A. Jones, Naoyuki Nishiya, Nyall 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

Research output: Contribution to journalArticle

Abstract

Slit-Roundabout (Robo) signalling has a well-understood role in axon guidance. 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. 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.

Original languageEnglish (US)
Pages (from-to)1325-1331
Number of pages7
JournalNature cell biology
Volume11
Issue number11
DOIs
StatePublished - Oct 26 2009
Externally publishedYes

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Paxillin
Blood Vessels
Vascular Diseases
ADP-Ribosylation Factors
Pathologic Neovascularization
GTPase-Activating Proteins
Retinal Diseases
Retinal Vessels
Monomeric GTP-Binding Proteins
Angiogenesis Inducing Agents
Nervous System
Maintenance
Proteins
Therapeutics

ASJC Scopus subject areas

  • Cell Biology

Cite this

Jones, C. A., Nishiya, N., London, N., Zhu, W., Sorensen, L. K., Chan, A. C., ... Li, D. Y. (2009). Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nature cell biology, 11(11), 1325-1331. https://doi.org/10.1038/ncb1976

Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. / Jones, Christopher A.; Nishiya, Naoyuki; London, Nyall; Zhu, Weiquan; Sorensen, Lise K.; Chan, Aubrey C.; Lim, Chinten J.; Chen, Haoyu; Zhang, Qisheng; Schultz, Peter G.; Hayallah, Alaa M.; Thomas, Kirk R.; Famulok, Michael; Zhang, Kang; Ginsberg, Mark H.; Li, Dean Y.

In: Nature cell biology, Vol. 11, No. 11, 26.10.2009, p. 1325-1331.

Research output: Contribution to journalArticle

Jones, CA, Nishiya, N, London, N, Zhu, W, Sorensen, LK, Chan, AC, Lim, CJ, Chen, H, Zhang, Q, Schultz, PG, Hayallah, AM, Thomas, KR, Famulok, M, Zhang, K, Ginsberg, MH & Li, DY 2009, 'Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity', Nature cell biology, vol. 11, no. 11, pp. 1325-1331. https://doi.org/10.1038/ncb1976
Jones, Christopher A. ; Nishiya, Naoyuki ; London, Nyall ; Zhu, Weiquan ; Sorensen, Lise K. ; Chan, Aubrey C. ; Lim, Chinten J. ; Chen, Haoyu ; Zhang, Qisheng ; Schultz, Peter G. ; Hayallah, Alaa M. ; Thomas, Kirk R. ; Famulok, Michael ; Zhang, Kang ; Ginsberg, Mark H. ; Li, Dean Y. / Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. In: Nature cell biology. 2009 ; Vol. 11, No. 11. pp. 1325-1331.
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