title: Functional and structural insights into ASB2alpha, a novel regulator of integrin-dependent adhesion of hematopoietic cells.
abstract: By providing contacts between hematopoietic cells and the bone marrow microenvironment, integrins are implicated in cell adhesion and thereby in control of cell fate of normal and leukemia cells. The ASB2 gene, initially identified as a retinoic acid responsive gene and a target of the promyelocytic leukemia retinoic acid receptor α oncoprotein in acute promyelocytic leukemia cells, encodes two isoforms, a hematopoietic-type (ASB2α) and a muscle-type (ASB2β) that are involved in hematopoietic and myogenic differentiation, respectively. ASB2α is the specificity subunit of an E3 ubiquitin ligase complex that targets filamins to proteasomal degradation. To examine the relationship of the ASB2α structure to E3 ubiquitin ligase function, functional assays and molecular modeling were performed. We show that ASB2α, through filamin A degradation, enhances adhesion of hematopoietic cells to fibronectin, the main ligand of β1 integrins. Furthermore, we demonstrate that a short N-terminal region specific to ASB2α, together with ankyrin repeats 1 to 10, is necessary for association of ASB2α with filamin A. Importantly, the ASB2α N-terminal region comprises a 9-residue segment with predicted structural homology to the filamin-binding motifs of migfilin and β integrins. Together, these data provide new insights into the molecular mechanisms of ASB2α binding to filamin.
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 205 route de Narbonne, 31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France.
authors: Isabelle
authors: I
authors: Lamsoul
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 205 route de Narbonne, 31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France.
authors: Clara F
authors: CF
authors: Burande
authors: Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Connecticut 06520.
authors: Ziba
authors: Z
authors: Razinia
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 205 route de Narbonne, 31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France.
authors: Thibault C
authors: TC
authors: Houles
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 205 route de Narbonne, 31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France.
authors: Delphine
authors: D
authors: Menoret
authors: Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Connecticut 06520.
authors: Massimiliano
authors: M
authors: Baldassarre
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 205 route de Narbonne, 31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France.
authors: Monique
authors: M
authors: Erard
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 205 route de Narbonne, 31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France.
authors: Christel
authors: C
authors: Moog-Lutz
authors: Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Connecticut 06520.
authors: David A
authors: DA
authors: Calderwood
authors: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 205 route de Narbonne, 31077 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31077 Toulouse, France. Electronic address: Pierre.Lutz@ipbs.fr.
authors: Pierre G
authors: PG
authors: Lutz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002448:Cell Adhesion; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D009132:Muscles / Q000378:metabolism; D041681:NIH 3T3 Cells; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
chemical_list: C437987:ASB2 protein, human; D048868:Adaptor Proteins, Signal Transducing; C542087:Asb2 protein, mouse; D002352:Carrier Proteins; D005353:Fibronectins; D016023:Integrins; D050826:Suppressor of Cytokine Signaling Proteins