The kinase domain of Drosophila Tribbles is required for turnover of fly C/EBP during cellmigration

Drosophila Tribbles (Trbl) encodes the founding member of the Trib family of kinase-like proteins that regulate cell migration, proliferation, growth and homeostasis. Trbl was identified in a misexpression screen in the ovary as an antagonist of border cell migration and acts in part by directing turnover of the C/EBP protein encoded by the gene slow border cells (slbo). The ability of mammalian Trib isoforms to promote C/EBP turnover during tissue differentiation indicates that this function is highly conserved. To better understand the role of Trbl in cell migration, we tested specific Trbl antisera, a trbl null allele and Trbl transgenes bearing site-directed mutations. Trbl is expressed at high levels in the nuclei of follicle cell epithelia and is downregulated in delaminating epithelia as expression of Slbo (C/EBP) is upregulated. This complementary pattern of expression during subsequent cell migration is achieved by negative feedback whereby slbo represses Trbl expression and trbl is necessary and sufficient to promote Slbo protein turnover. A series of point mutations that scan the conserved kinase domain of Trbl reveal that the conserved DLK catalytic loop is required for Trbl–Slbo binding and turnover, as well as for interactions between Trbl subunits, suggesting a mechanism of Trbl function.

► Negative feedback between Trbl and Slbo occurs during cell migration.
► Catalytic loop of the atypical kinase Trbl is required for turnover of C/EBP Slbo.
► Trbl–Slbo interactions are compromised by mutations in the catalytic loop.
► Trbl–Trbl interactions suggest autoinhibitory homodimers.