ASB2 targets filamins A and B to proteasomal degradation

Author:

Heuzé Mélina L.12,Lamsoul Isabelle12,Baldassarre Massimiliano3,Lad Yatish3,Lévêque Sophie12,Razinia Ziba4,Moog-Lutz Christel125,Calderwood David A.3,Lutz Pierre G.12

Affiliation:

1. Université de Toulouse, Université Paul Sabatier, Toulouse, France;

2. Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France;

3. Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, and

4. Department of Cell Biology, School of Medicine, Yale University, New Haven, CT; and

5. Université Pierre et Marie Curie, Paris, France

Abstract

Abstract The ordered series of proliferation and differentiation from hematopoietic progenitor cells is disrupted in leukemia, resulting in arrest of differentiation at immature proliferative stages. Characterizing the molecular basis of hematopoietic differentiation is therefore important for understanding and treating disease. Retinoic acid induces expression of ankyrin repeat-containing protein with a suppressor of cytokine signaling box 2 (ASB2) in acute promyelocytic leukemia cells, and ASB2 expression inhibits growth and promotes commitment, recapitulating an early step critical for differentiation. ASB2 is the specificity subunit of an E3 ubiquitin ligase complex and is proposed to exert its effects by regulating the turnover of specific proteins; however, no ASB2 substrates had been identified. Here, we report that ASB2 targets the actin-binding proteins filamin A and B for proteasomal degradation. Knockdown of endogenous ASB2 in leukemia cells delays retinoic acid-induced differentiation and filamin degradation; conversely, ASB2 expression in leukemia cells induces filamin degradation. ASB2 expression inhibits cell spreading, and this effect is recapitulated by knocking down both filamin A and filamin B. Thus, we suggest that ASB2 may regulate hematopoietic cell differentiation by modulating cell spreading and actin remodeling through targeting of filamins for degradation.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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