Journal
JOURNAL OF CELL SCIENCE
Volume 119, Issue 3, Pages 425-432Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.02755
Keywords
GTPase-activating protein; ARAP3; PI3K; Rho; Arf; lamellipodium
Categories
Funding
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C219, BBS/E/B/00001219] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BBS/E/B/0000C219, BBS/E/B/00001219] Funding Source: Medline
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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)P-3], 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)P-3 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.
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