Keratin 19 interacts with GSK3 beta to regulate its nuclear accumulation and degradation of cyclin D3

Cyclin D3 regulates the G1/S transition and is frequently overexpressed in several cancer types including breast cancer, where it promotes tumor progression. Here we show that a cytoskeletal protein keratin 19 (K19) physically interacts with a serine/threonine kinase GSK3 beta and prevents GSK3 beta-dependent degradation of cyclin D3. The absence of K19 allowed active GSK3 beta to accumulate in the nucleus and degrade cyclin D3. Specifically, the head (H) domain of K19 was required to sustain inhibitory phosphorylation of GSK3 beta Ser9, prevent nuclear accumulation of GSK3 beta, and maintain cyclin D3 levels and cell proliferation. K19 was found to interact with GSK3 beta and K19-GSK3 beta interaction was mapped out to require Ser10 and Ser35 residues on the H domain of K19. Unlike wildtype K19, S10A and S35A mutants failed to maintain total and nuclear cyclin D3 levels and induce cell proliferation. Finally, we show that the K19-GSK3 beta-cyclin D3 pathway affected sensitivity of cells toward inhibitors to cyclin-dependent kinase 4 and 6 (CDK4/6). Overall, these findings establish a role for K19 in the regulation of GSK3 beta-cyclin D3 pathway and demonstrate a potential strategy for overcoming resistance to CDK4/6 inhibitors.