Journal
CURRENT BIOLOGY
Volume 16, Issue 3, Pages 315-320Publisher
CELL PRESS
DOI: 10.1016/j.cub.2005.12.032
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Funding
- NCI NIH HHS [P30 CA044579, P30 CA44579] Funding Source: Medline
- NIDDK NIH HHS [DK58536, R01 DK058536] Funding Source: Medline
- NIGMS NIH HHS [GM66251, R01 GM066251] Funding Source: Medline
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The small GTPase Arf6 has been shown to regulate the post-endocytic trafficking of a subset of membrane proteins, including beta 1 integrins, and inhibition of Arf6 function impairs both cell adhesion and motility [1]. The activity of Arf GTPases is regulated by a large family of guanine nucleotide exchange factors (GEFs) [2]. Arf-GEP100/BRAG2 is a GEF with reported specificity for Arf6 in vitro [3], but it is otherwise poorly characterized. Here we report that BRAG2 exists in two ubiquitously expressed isoforms, which we call BRAG2a and BRAG2b, both of which can activate Arf6 in vivo. Depletion of endogenous BRAG2 by siRNA leads to dramatic effects in the cell periphery; one such effect is an accumulation of beta 1 integrin on the cell surface and a corresponding enhancement of cell attachment and spreading on fibronectin-coated substrates. In contrast, depletion of Arf6 leads to intracellular accumulation of beta 1 integrin and reduced adhesion and spreading. These findings suggest that Arf6 regulates both endocytosis and recycling of beta 1 integrins and that BRAG2 functions selectively to activate Arf6 during integrin internalization.
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