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Rab5 is a signalling GTPase involved in actin remodelling by receptor tyrosine kinases

Nature volume 429, pages 309–314 (2004)Cite this article

Abstract

Rab5 is a small GTPase involved in the control of intracellular trafficking, both at the level of receptor endocytosis and endosomal dynamics1. The finding that Rab5 can be activated by receptor tyrosine kinases (RTK)2 raised the question of whether it also participates in effector pathways emanating from these receptors. Here we show that Rab5 is indispensable for a form of RTK-induced actin remodelling, called circular ruffling. Three independent signals, originating from Rab5, phosphatidylinositol-3-OH kinase and Rac, respectively, are simultaneously required for the induction of circular ruffles. Rab5 signals to the actin cytoskeleton through RN-tre, a previously identified Rab5-specific GTPase-activating protein (GAP)3. Here we demonstrate that RN-tre has the dual function of Rab5-GAP and Rab5 effector. We also show that RN-tre is critical for macropinocytosis, a process previously connected to the formation of circular ruffles4,5. Finally, RN-tre interacts with both F-actin and actinin-4, an F-actin bundling protein. We propose that RN-tre establishes a three-pronged connection with Rab5, F-actin and actinin-4. This may aid crosslinking of actin fibres into actin networks at the plasma membrane. Thus, we have shown that Rab5 is a signalling GTPase and have elucidated the major molecular elements of its downstream pathway.

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Figure 1: Rab5 and circular ruffles.
Figure 2: Biological effects of RN-tre and its mutants.
Figure 3: Interaction between RN-tre and ACTN4.
Figure 4: Role of RN-tre and ACTN4 in circular ruffling.

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Acknowledgements

This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro and Human Science Frontier Program to P.P.D.F. and G.S., and by grants from the Association for International Cancer Research, European Community (VI Framework), Italian Ministry for University and Research and Consiglio Nazionale delle Ricerche to P.P.D.F. We thank E. Frittoli for technical assistance. L.L. was supported in part by a fellowship from the Associazione Sviluppo Piemonte.

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Authors and Affiliations

  1. Istituto Europeo di Oncologia, Via Ripamonti 435, 20141, Milan, Italy

    Letizia Lanzetti, Andrea Palamidessi, Liliana Areces, Giorgio Scita & Pier Paolo Di Fiore

  2. IFOM, Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139, Milan, Italy

    Andrea Palamidessi, Liliana Areces, Giorgio Scita & Pier Paolo Di Fiore

  3. Dipartimento di Medicina, Chirurgia ed Odontoiatria, Universita' degli Studi di Milano, 20122, Milan, Italy

    Pier Paolo Di Fiore

Authors
  1. Letizia Lanzetti
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  2. Andrea Palamidessi
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  5. Pier Paolo Di Fiore
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Correspondence to Pier Paolo Di Fiore.

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Supplementary information

Supplementary Figure S1

Active Ras and Rac induce lamellipodia, but not circular ruffles. (PDF 2509 kb)

Supplementary Figure S2

Coated pit-mediated endocytosis and PDGF-induced circular ruffling are independent events. (PDF 3610 kb)

Supplementary Figure S3

Effects of Rab5 and various GTPases and their effectors on the actin cytoskeleton. (PDF 4816 kb)

Supplementary Figure S4

Involvement of RN-tre in circular ruffling and macropinocytosis. (PDF 17070 kb)

Supplementary Figure Legends (DOC 33 kb)

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Lanzetti, L., Palamidessi, A., Areces, L. et al. Rab5 is a signalling GTPase involved in actin remodelling by receptor tyrosine kinases. Nature 429, 309–314 (2004). https://doi.org/10.1038/nature02542

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