Phosphorylation of serine 323 of ASB2¦Á is pivotal for the targeting of filamin A to degradation

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• 作者：Rim Zakaria ; Isabelle Lamsoul ; S ; rine Uttenweiler-Joseph ; Monique Erard ; Bernard Monsarrat ; Odile Burlet-Schiltz ; Christel Moog-Lutz ; Pierre G. Lutz
• 关键词：AML ; acute myeloid leukemia ; APL ; acute promyelocytic leukemia ; AR ; ankyrin repeat ; CID ; collision-induced dissociation ; CRL5 ; cullin5-RING E3 ubiquitin ligases ; Erk ; extracellular signal-regulated kinase ; ETD ; electron transfer dissociation ; E3 ; E3 ubiqu
• 刊名：Cellular Signalling
• 出版年：2013
• 出版时间：December, 2013
• 年：2013
• 卷：25
• 期：12
• 页码：2823-2830
• 全文大小：1460 K

文摘

ASB proteins are the specificity subunits of cullin5-RING E3 ubiquitin ligases (CRL5) that play roles in ubiquitin-mediated protein degradation. However, how their activity is regulated remains poorly understood. Here, we unravel a novel mechanism of regulation of a CRL5 through phosphorylation of its specificity subunit ASB2¦Á. Indeed, using mass spectrometry, we showed for the first time that ASB2¦Á is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2¦Á is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. Mutation of ASB2¦Á Ser-323 to Ala had no effect on intrinsic E3 ubiquitin ligase activity of ASB2¦Á but abolished the ability of ASB2¦Á to induce degradation of FLNa. In contrast, the ASB2¦Á Ser-323 to Asp phosphomimetic mutant induced acute degradation of FLNa. Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2¦Á-mediated FLNa degradation. We further showed that the subcellular localization of ASB2¦Á to actin-rich structures is dependent on ASB2¦Á Ser-323 phosphorylation and propose that the interaction with FLNa depends on the electrostatic potential redistribution induced by the Ser-323 phosphate group. Taken together, these data unravel an important mechanism by which ASB2¦Á-mediated FLNa degradation can be regulated.