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First published online 17 January 2006
doi: 10.1242/jcs.02755

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ARAP3 is essential for formation of lamellipodia after growth factor stimulation

The Inositide Laboratory, The Babraham Institute, Cambridge, CB2 4AT, UK

^* Author for correspondence (e-mail: sonja.krugmann{at}bbsrc.ac.uk)

Accepted 24 October 2005

Rho and Arf family small GTPases control dynamic actin rearrangements and vesicular trafficking events. ARAP3 is a dual GAP for RhoA and Arf6 that is regulated by phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P₃], a product of the phosphoinositide 3-kinase (PI3K) signalling pathway. To investigate the physiological function of ARAP3, we used an RNAi-based approach in an endothelial cell model. ARAP3-deficient cells showed increased activities of RhoA and Arf6. Phenotypically, they were more rounded than control counterparts and displayed very fine stress fibres. ARAP3-deficient cells were not capable of producing lamellipodia upon growth factor stimulation, a process known to depend on PI3K and Rac activities. Rac was transiently activated in stimulated ARAP3 RNAi cells although its cellular localisation was altered, a likely consequence of increased Arf6 activity. We conclude that ARAP3 recruitment to sites of elevated PtdIns(3,4,5)P₃ is crucial to allow localised inactivation of RhoA and cycling of Arf6, both of which are necessary to allow growth factor-stimulated formation of lamellipodia.

Key words: GTPase-activating protein, ARAP3, PI3K, Rho, Arf, Lamellipodium

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