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Cell Signal. 2013 Dec;25(12):2823-30. doi: 10.1016/j.cellsig.2013.09.011. Epub 2013 Sep 15.

Phosphorylation of serine 323 of ASB2α is pivotal for the targeting of filamin A to degradation.

Author information

1
CNRS; IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne BP 64182, F-31077 Toulouse, France; Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France.

Abstract

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 ASB2α. Indeed, using mass spectrometry, we showed for the first time that ASB2α is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2α is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. Mutation of ASB2α Ser-323 to Ala had no effect on intrinsic E3 ubiquitin ligase activity of ASB2α but abolished the ability of ASB2α to induce degradation of FLNa. In contrast, the ASB2α 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 ASB2α-mediated FLNa degradation. We further showed that the subcellular localization of ASB2α to actin-rich structures is dependent on ASB2α 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 ASB2α-mediated FLNa degradation can be regulated.

KEYWORDS:

AML; APL; AR; ASB; CID; CRL5; Cullin-RING E3 ubiquitin ligase; E3; E3 ubiquitin ligase; ETD; Erk; FLN; Filamin; Mass spectrometry; Post-translational modifications; acute myeloid leukemia; acute promyelocytic leukemia; ankyrin repeat; collision-induced dissociation; cullin5-RING E3 ubiquitin ligases; electron transfer dissociation; extracellular signal-regulated kinase; filamin

PMID:
24044920
DOI:
10.1016/j.cellsig.2013.09.011
[Indexed for MEDLINE]

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