TAILIEUCHUNG - Báo cáo khoa học: Activated Rac1, but not the tumorigenic variant Rac1b, is ubiquitinated on Lys 147 through a JNK-regulated process

Ubiquitination and proteasomal degradation have recently emerged as an additional level of regulation of activated forms of Rho GTPases. To char-acterize this novel regulatory pathway and to gain insight into its biological significance, we studied the ubiquitination of two constitutively activated forms of Rac1, . | ễFEBS Journal Activated Rac1 but not the tumorigenic variant Raclb is ubiquitinated on Lys 147 through a JNK-regulated process Orane Visvikis1 2 Patrick Lores1 2 Laurent Boyer3 Pierre Chardin4 Emmanuel Lemichez3 and Gerard Gacon1 2 1 Institut Cochin Université Paris Descartes CNRS UMR8104 Paris France 2 INSERM U567 Paris France 3 Faculte de Medecine INSERM U627 Nice France 4 Institut de Pharmacologie du CNRS Sophia Antipolis France Keywords JNK Raclb Rho GTPases ubiquitination Correspondence G. Gacon Institut Cochin Departement Genetique et Developpement 24 rue du Faubourg Saint-Jacques 75014 Paris France Fax 33 1 44 41 24 41 Tel 33 1 44 41 24 70 E-mail gacon@ Received 29 August 2007 revised 18 November 2007 accepted 27 November 2007 doi Ubiquitination and proteasomal degradation have recently emerged as an additional level of regulation of activated forms of Rho GTPases. To characterize this novel regulatory pathway and to gain insight into its biological significance we studied the ubiquitination of two constitutively activated forms of Rac1 . the mutationally activated Rac1L61 and the tumori-genic splice variant Rac1b which is defective for several downstream signaling pathways including JNK activation. Whereas Rac1L61 undergoes polyubiquitination and subsequent proteasomal degradation in HEK293 cells Rac1b is poorly ubiquitinated and appears to be much more resistant to proteasomal degradation than Rac1L61. Mutational analysis of all lysine residues in Rac1 revealed that the major target site for Rac1 ubiquitination is Lys147 a solvent-accessible residue that has a similar conformation in Rac1b. Like Rac1L61 Rac1b was found to be largely associated with plasma membrane a known prerequisite for Rac1 ubiquitination. Interestingly Rac1b ubiquitination could be stimulated by coexpression of Rac1L61 suggesting positive regulation of Rac1 ubiquitination by Rac1 downstream signaling. Indeed ubiquitination of Rac1L61

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