ASB2 targets filamins A and B to proteasomal degradation.
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.
Heuzé
Mélina L
ML
Université de Toulouse, Université Paul Sabatier, Toulouse, France.
Lamsoul
Isabelle
I
Baldassarre
Massimiliano
M
Lad
Yatish
Y
Lévêque
Sophie
S
Razinia
Ziba
Z
Moog-Lutz
Christel
C
Calderwood
David A
DA
Lutz
Pierre G
PG
D000199:Actins / Q000378:metabolism; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D064448:Filamins; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology
C437987:ASB2 protein, human; D000199:Actins; D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D050826:Suppressor of Cytokine Signaling Proteins; D014212:Tretinoin; D046988:Proteasome Endopeptidase Complex
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