Abstract
The ASB2α protein is the specificity subunit of an E3 ubiquitin ligase complex involved in hematopoietic differentiation and is proposed to exert its effects by regulating the turnover of specific proteins. Three ASB2α substrates have been described so far: the actin-binding protein filamins, the Mixed Lineage Leukemia protein, and the Janus kinases 2 and 3. To determine the degradation of which substrate drives ASB2α biological effects is crucial for the understanding of ASB2α functions in hematopoiesis. Here, we show that neither endogenous nor exogenously expressed ASB2α induces degradation of JAK proteins in hematopoietic cells. Furthermore, we performed molecular modeling to generate the first structural model of an E3 ubiquitin ligase complex of an ASB protein bound to one of its substrates.
Highlights
Ubiquitin-mediated protein degradation is the main mechanism for controlled proteolysis in Eukaryotes and ensures that specific protein functions are turned off at the right time and in the right place through the selective targeting of proteins to proteasome
ASB2a transcripts were initially identified in acute promyelocytic leukemia (APL) cells induced to differentiate by retinoic acid, they are expressed in normal hematopoietic cells [5,7,8] and so ASB2a is likely to be relevant during hematopoiesis
Because ASB2a was originally identified as induced by retinoic acid in acute myeloid leukemia cells [5,7], we investigated the expression of Janus kinases (JAK) proteins known to be expressed in these cells [17]
Summary
Ubiquitin-mediated protein degradation is the main mechanism for controlled proteolysis in Eukaryotes and ensures that specific protein functions are turned off at the right time and in the right place through the selective targeting of proteins to proteasome. We have showed that ASB2a E3 ubiquitin ligase activity triggers polyubiquitylation of the actin-binding protein filamins (FLNa, FLNb and FLNc) leading to their proteasome-mediated degradation [6,12,13]. The Janus kinases (JAK) 2 and 3 that are crucial for cytokine receptor signaling during hematopoiesis were proposed to be substrates of a non-canonical E3 ubiquitin ligase complex including ASB2a and the F-box containing protein Skp2 [15,16].
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