article accepted in JBC
Elevated Protein Kinase D3 (PKD3) expression supports proliferation of triple-negative breast cancer cells and contributes to mTORC1-S6K1 pathway activation
Bettina Huck 1, Stephan Duss 2, Angelika Hausser 1 and Monilola A. Olayioye 1*
1Institute of Cell Biology and Immunology, University Stuttgart, Allmandring 31, 70569 Stuttgart, Germany
2Friedrich Miescher Institute of Medical Research, Switzerland
*Corresponding author; email: email@example.com
Here we show that the expression of the Golgi-localized serine-threonine kinase Protein Kinase D 3 (PKD3) is elevated in triple-negative breast cancer (TNBC). Using an antibody array, we identified PKD3 to trigger the activation of S6 kinase 1 (S6K1), a main downstream target of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Accordingly, PKD3 knockdown in TNBC cells led to reduced S6K1 phosphorylation, which was associated with impaired activation of mTORC1 at endolysosomal membranes, the accumulation of the M6P receptor in and the recruitment of the autophagy marker LC3 to enlarged acidic vesicles. We further show that PKD3 depletion strongly inhibited cell spreading and proliferation of TNBC cells, identifying this kinase as a potential novel molecular therapeutic target in TNBC. Together, our data suggest that PKD3 in TNBC cells provides a molecular connection between the Golgi and endolysosomal compartments to enhance proliferative mTORC1-S6K1 signaling.