Elevated protein kinase D3 (PKD3) expression supports proliferation of triple-negative breast cancer cells and contributes to mTORC1-S6K1 pathway activation.

Abstract

Here, we show that the expression of the Golgi-localized serine-threonine kinase protein kinase D3 (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 mannose 6-phosphate receptor in and the recruitment of the autophagy marker light chain 3 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.

• Authors: Bettina Huck, Stephan Duss, Angelika Hausser, Monilola A Olayioye
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 6 Pg. 3138-47 (Feb 07 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24337579 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Multiprotein Complexes
• Neoplasm Proteins
• protein kinase C nu
• Mechanistic Target of Rapamycin Complex 1
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• ribosomal protein S6 kinase, 70kD, polypeptide 1
• Protein Kinase C

Topics

• Breast Neoplasms (genetics, metabolism, pathology, therapy)
• Cell Line, Tumor
• Cell Proliferation
• Endosomes (genetics, metabolism, pathology)
• Female
• Gene Knockdown Techniques
• Golgi Apparatus (genetics, metabolism, pathology)
• Humans
• Lysosomes (genetics, metabolism, pathology)
• Mechanistic Target of Rapamycin Complex 1
• Multiprotein Complexes (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Protein Kinase C (biosynthesis, genetics)
• Ribosomal Protein S6 Kinases, 70-kDa (genetics, metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (genetics, metabolism)