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  • br Six Ankyrin Repeat Domain Containing


    Six-Ankyrin Repeat Domain-Containing ASB Proteins Asb family members contain a relatively divergent N-terminal domain, followed by a varying number of ankyrin repeats and a C-terminal SOCS box (Figure 3). Asb11 contains six ankyrin repeats, a feature that it shares with Asb5, Asb9, and Asb13, suggesting that these proteins constitute a separate subgroup within the Asb family of proteins. Analysis of the primary sequence shows high homology in the N-terminal domain (i.e., the Lestaurtinib receptor in the N terminus of the ankyrin repeats, the most divergent region in the Asb family) of these four proteins, and analysis of the intron/exon boundaries also supports the notion that these six-ankyrin repeat domain-containing proteins are a separate subgroup within the Asb gene family. Homology is even higher in the 3′ untranslated region [17]. Furthermore, overexpression of ASB5, ASB9, and ASB11, but not of ASB1, ASB2, or ASB15, activates a Notch reporter construct in HeLa cells, demonstrating that members of the six-ankyrin repeat subfamily of Asb genes share functional characteristics that certain other Asb family members do not have. Functionally, these six-ankyrin repeat domain-containing Asb genes may all be involved in compartment size regulation. The expression pattern of d-asb9/11 in D. rerio revealed high expression during myogenesis. Forced expression of d-asb9/11 impaired terminal differentiation and caused hyperproliferation in the myogenic progenitor compartment, whereas either knockdown of d-asb9/11 or introduction of a germline mutation in the zebrafish d-asb9/11 gene (asb9/11cul) produced premature differentiation of muscle progenitors. Finally, d-asb9cul mutant fish were severely impaired in regenerative responses. Thus, d-asb9/11 is a principal regulator of both embryonic and regenerative myogenesis; in addition, six-ankyrin repeat domain-containing Asb proteins can act outside the ectodermal lineage and may also be active in derivatives from the mesodermal germline with respect to compartment expansion 18, 19. Most of the data indicating that the six-ankyrin repeat domain-containing Asb genes drive compartment expansion come from zebrafish and concern Asb11. However, there is evidence to suggest that these data can be expanded to the entire vertebrate phylum and to all six-ankyrin repeat domain-containing Asb genes. As discussed above, in human neuronal systems, heterologous expression of ASB11 can also drive compartment expansion, whereas in murine myoblasts, all six-ankyrin repeat domain-containing Asb genes drive such expansion. In addition, Asb5, Asb9, Asb11, and Asb13 can all drive compartment expansion in the untransformed mammalian gastrointestinal system and show possible deregulation in gastrointestinal cancer [20]. The apparent importance of these six-ankyrin repeat domain-containing ASB proteins in compartment expansion prompts us to review their function here.
    Asb genes were originally identified in mice, but have since been found in all members of the Chordata investigated; however, no obvious relatives of Asb genes have been identified in nonchordates. Nevertheless, a bioinformatical search (M. Peppelenbosch, 2018) revealed more than 4000 different Asb orthologs and paralogs that have been found in humans, mice, rabbits, and even the African toad. Asb genes are classified as belonging to the SOCS-box superfamily, which is a group of genes acting as ubiquitin E3 ligases and mediating ubiquitination (Box 2). Within the Asb family, the six-ankyrin repeat domain-containing proteins are evolutionarily the most ancient because they are the only ones found in nonvertebrates. The remarkable differences in primary sequence and gene structure suggest that the non-six-ankyrin repeat domain-containing Asb proteins arose as a result of parallel evolution rather than being descended from the six-ankyrin repeat domain-containing Asb genes. Functionally, however, there are important similarities [21].