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First published online June 20, 2006
doi: 10.1242/10.1242/jcs.02996

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ßPIX controls cell motility and neurite extension by regulating the distribution of GIT1

Lorena Za¹, Chiara Albertinazzi^1,*, Simona Paris¹, Mariacristina Gagliani², Carlo Tacchetti² and Ivan de Curtis^1,

¹ Cell Adhesion Unit, Department of Molecular Biology and Functional Genomics, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milano, Italy
² MicroScoBio Research Center and IFOM Center for Cell Oncology and Ultrastructure, Department of Experimental Medicine, University of Genoa, Via deToni 14, 16132, Genoa, Italy

Author for correspondence (e-mail: decurtis.ivan{at}hsr.it)

Accepted 27 March 2006

Cell motility entails the reorganization of the cytoskeleton and membrane trafficking for effective protrusion. GIT1/p95-APP1 is a member of a family of GTPase-activating proteins for ARF GTPases that affect endocytosis, adhesion and migration. GIT1 associates with paxillin and a complex including the Rac/Cdc42 exchanging factors PIX/Cool and the kinase PAK. In this study, we show that overexpression of ßPIX induces the accumulation of endogenous and overexpressed GIT1 at large structures similar to those induced by an ArfGAP-defective mutant of GIT1 (p95-C2). Immunohistochemical analysis and immunoelectron microscopy reveal that these structures include the endogenous transferrin receptor. Time-lapse analysis during motogenic stimuli shows that the formation and perinuclear accumulation of the p95-C2-positive structures is paralleled by inhibition of lamellipodium formation and cell retraction. Both dimerization and a functional SH3 domain of ßPIX are required for the accumulation of GIT1 in fibroblasts, which is prevented by the monomeric PIX-PG-LZ. This mutant also prevents the formation of endocytic aggregates and inhibition of neurite outgrowth in retinal neurons expressing p95-C2. Our results indicate that ßPIX is an important regulator of the subcellular distribution of GIT1, and suggest that alteration in the level of expression of the complex affects the endocytic compartment and cell motility.

Key words: ArfGAP, GTPases, Membrane traffic, Motility, Neuritogenesis

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