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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 ? oncoprotein in acute promyelocytic leukemia cells, encodes two isoforms, a hematopoietic-type (ASB2?) and a muscle-type (ASB2?) that are involved in hematopoietic and myogenic differentiation, respectively. ASB2? is the specificity subunit of an E3 ubiquitin ligase complex that targets filamins to proteasomal degradation. To examine the relationship of the ASB2? structure to E3 ubiquitin ligase function, functional assays and molecular modeling were performed. We show that ASB2?, through filamin A degradation, enhances adhesion of hematopoietic cells to fibronectin, the main ligand of ?1 integrins. Furthermore, we demonstrate that a short N-terminal region specific to ASB2?, together with ankyrin repeats 1 to 10, is necessary for association of ASB2? with filamin A. Importantly, the ASB2? N-terminal region comprises a 9-residue segment with predicted structural homology to the filamin-binding motifs of migfilin and ? integrins. Together, these data provide new insights into the molecular mechanisms of ASB2? binding to filamin.

SUBMITTER: Lamsoul I

PROVIDER: S-EPMC3162417 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Functional and structural insights into ASB2alpha, a novel regulator of integrin-dependent adhesion of hematopoietic cells.

Lamsoul Isabelle I Burande Clara F CF Razinia Ziba Z Houles Thibault C TC Menoret Delphine D Baldassarre Massimiliano M Erard Monique M Moog-Lutz Christel C Calderwood David A DA Lutz Pierre G PG

The Journal of biological chemistry 20110707 35

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 an ...[more]

PMID: 21737450

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Project description:Integrin-mediated adhesion is a central feature of cellular adhesion, locomotion, and endothelial cell mechanobiology. Although integrins are known to be transmembrane proteins, little is known about the role of membrane biophysics and dynamics in integrin adhesion. We treated human aortic endothelial cells with exogenous amphiphiles, shown previously in model membranes, and computationally, to affect bilayer thickness and lipid phase separation, and subsequently measured single-integrin-molecule adhesion kinetics using an optical trap, and diffusion using fluorescence correlation spectroscopy. Benzyl alcohol (BA) partitions to liquid-disordered (Ld) domains, thins them, and causes the greatest increase in hydrophobic mismatch between liquid-ordered (Lo) and Ld domains among the three amphiphiles, leading to domain separation. In human aortic endothelial cells, BA increased ?1-integrin-Arg-Gly-Asp-peptide affinity by 18% with a transition from single to double valency, consistent with a doubling of the molecular brightness of mCherry-tagged ?1-integrins measured using fluorescence correlation spectroscopy. Accordingly, BA caused an increase in the size of focal-adhesion-kinase/paxillin-positive peripheral adhesions and reduced migration speeds as measured using wound-healing assays. Vitamin E, which thickens Lo domains and disperses them by lowering edge energy on domain boundaries, left integrin affinity unchanged but reduced binding probability, leading to smaller focal adhesions and equivalent migration speed relative to untreated cells. Vitamin E reversed the BA-induced decrease in migration speed. Triton X-100 also thickens Lo domains, but partitions to both lipid phases and left unchanged binding kinetics, focal adhesion sizes, and migration speed. These results demonstrate that only the amphiphile that thinned Ld lipid domains increased ?1-integrin-Arg-Gly-Asp-peptide affinity and valency, thus implicating Ld domains in modulation of integrin adhesion, nascent adhesion formation, and cell migration.

Dataset Information

Functional and structural insights into ASB2alpha, a novel regulator of integrin-dependent adhesion of hematopoietic cells.

Publications

Functional and structural insights into ASB2alpha, a novel regulator of integrin-dependent adhesion of hematopoietic cells.

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