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J. Biol. Chem., Vol. 280, Issue 39, 33200-33205, September 30, 2005
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From the Department of Physiological Chemistry and Centre of Biomedical Genetics, University Medical Centre, Utrecht 3508 AB, The Netherlands
AF6 is involved in the connection of membrane-associated proteins to the actin cytoskeleton. It binds to Ras-like small GTPases and is suggested to be an effector of both Ras and Rap. Here we show that knockdown of AF6 in T cells by RNA interference enhanced Rap1-induced integrin-mediated cell adhesion, whereas overexpression of AF6 had the opposite effect. Interestingly, AF6-induced inhibition of cell adhesion correlated with an increase in RapGTP levels. Like AF6, protein KIAA1849 contains a Ras association domain and interacted with Rap1. However, KIAA1849 did not inhibit Rap1-induced cell adhesion. We concluded that AF6 is a negative regulator of Rap-induced cell adhesion. We proposed that AF6 inhibits Rap-mediated cell adhesion by sequestering RapGTP in an unproductive complex and thus prevents the interaction of Rap1 not only with effectors that mediate adhesion but also with Rap GTPase-activating proteins. Thus, AF6 may buffer RapGTP in resting T cells and maintain them in a non-adherent state.
Received for publication, May 9, 2005 , and in revised form, July 12, 2005.
* This work is supported by the Netherlands Genomics Initiative through the Cancer Genomics Center (to Z. Z.), the Dutch Cancer Society (KWF) (to L. S. P.), and Chemical Sciences of the Netherlands Organization for Scientific Research (NWO-CW) (to H. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Dept. of Physiological Chemistry and Centre of Biomedical Genetics, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. Tel.: 31-30-2538988; Fax: 31-30-2539035; E-mail: J.L.Bos{at}med.uu.nl.
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