Protein Kinase D1 Mediates Anchorage-dependent and -independent Growth of Tumor Cells via the Zinc Finger Transcription Factor Snail1

• Published in: The Journal of biological chemistry Vol. 287; no. 39; pp. 32367 - 32380
• Main Authors: Eiseler, Tim, Köhler, Conny, Nimmagadda, Subbaiah Chary, Jamali, Arsia, Funk, Nancy, Joodi, Golsa, Storz, Peter, Seufferlein, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.09.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Active Transport, Cell Nucleus - genetics; Amino Acid Oxidoreductases; Cell Biology; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Proliferation; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cytoplasm - genetics; Cytoplasm - metabolism; HEK293 Cells; HeLa Cells; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Histone Deacetylase 2 - genetics; Histone Deacetylase 2 - metabolism; Humans; LIM Domain Proteins - genetics; LIM Domain Proteins - metabolism; Neoplasms - genetics; Neoplasms - metabolism; Pancreatic Cancer; Proliferation; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein Kinase D (PKD); Snail Family Transcription Factors; Transcription Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Transcription Factors; Pancreatic Cancer; Proliferation; Protein Kinase D (PKD); Cell Biology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.370999

We here identify protein kinase D1 (PKD1) as a major regulator of anchorage-dependent and -independent growth of cancer cells controlled via the transcription factor Snail1. Using FRET, we demonstrate that PKD1, but not PKD2, efficiently interacts with Snail1 in nuclei. PKD1 phosphorylates Snail1 at Ser-11. There was no change in the nucleocytoplasmic distribution of Snail1 using wild type Snail1 and Ser-11 phosphosite mutants in different tumor cells. Regardless of its phosphorylation status or following co-expression of constitutively active PKD, Snail1 was predominantly localized to cell nuclei. We also identify a novel mechanism of PKD1-mediated regulation of Snail1 transcriptional activity in tumor cells. The interaction of the co-repressors histone deacetylases 1 and 2 as well as lysyl oxidase-like protein 3 with Snail1 was impaired when Snail1 was not phosphorylated at Ser-11, which led to reduced Snail1-associated histone deacetylase activity. Additionally, lysyl oxidase-like protein 3 expression was up-regulated by ectopic PKD1 expression, implying a synergistic regulation of Snail1-driven transcription. Ectopic expression of PKD1 also up-regulated proliferation markers such as Cyclin D1 and Ajuba. Accordingly, Snail1 and its phosphorylation at Ser-11 were required and sufficient to control PKD1-mediated anchorage-independent growth and anchorage-dependent proliferation of different tumor cells. In conclusion, our data show that PKD1 is crucial to support growth of tumor cells via Snail1. Background: The protein kinase D (PKD) family is involved in the control of cell motility and proliferation. Results: PKD1 controls growth of cancer cells through phosphorylation of Snail1 at Ser-11. Conclusion: Only PKD1, but not PKD2, mediates isoform-specific control of pancreatic cancer cell proliferation through Snail1. Significance: We demonstrate for the first time isoform-specific control of pancreatic cancer growth by a single phosphorylation of a substrate.