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The Scaffolding Protein CG-NAP/AKAP450 Is a Critical Integrating Component of the LFA-1-Induced Signaling Complex in Migratory T Cells¹

Basma Salah El Din El Homasany^2,*, Yuri Volkov^2,3,*, Mikiko Takahashi, Yoshitaka Ono, Guy Keryer, Annie Delouvée, Eileen Looby^*, Aideen Long^2, and Dermot Kelleher^2,*

^* Department of Clinical Medicine, Trinity College, Dublin Molecular Medicine Center, Dublin, Ireland; Biosignal Research Center, Kobe University, Kobe, Japan; Unité Mixte Recherche 144-Centre National de la Recherche Scientifique-Institut Curie, Paris, France; and Department of Biochemistry, Royal College of Surgeons of Ireland, Dublin, Ireland

T cell migration represents a complex highly coordinated process involving participation of surface receptor/ligand interactions, cytoskeletal rearrangements, and phosphorylation-dependent signaling cascades. Members of the A-kinase anchoring protein (AKAP) family of giant scaffolding proteins can assemble and compartmentalize multiple signaling and structural molecules thereby providing a platform for their targeted positioning and efficient interactions. We characterize here the expression, intracellular distribution, and functional role of the scaffolding protein CG-NAP (centrosome and Golgi localized protein kinase N-associated protein)/AKAP450 in the process of active T cell motility induced via LFA-1 integrins. This protein is predominantly localized at the centrosome and Golgi complex. T cell locomotion triggered by LFA-1 ligation induces redistribution of CG-NAP/AKAP450 along microtubules in trailing cell extensions. Using an original in situ immunoprecipitation approach, we show that CG-NAP/AKAP450 is physically associated with LFA-1 in the multimolecular signaling complex also including tubulin and the protein kinase C and isoenzymes. CG-NAP/AKAP450 recruitment to this complex was specific for the T cells migrating on LFA-1 ligands, but not on the ₁ integrin ligand fibronectin. Using the GFP-tagged C-terminal CG-NAP/AKAP450 construct, we demonstrate that expression of the intact CG-NAP/AKAP450 and its recruitment to the LFA-1-associated multimolecular complex is critically important for polarization and migration of T cells induced by this integrin.