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Papers In Press, published online ahead of print December 10, 2002
Section on Cancer Biology, National Center for Cell Science, Pune, Maharashtra 411007
Corresponding Author: gopalkundu{at}hotmail.com
Tumor growth and metastasis are multifaceted processes which mainly involves in cell adhesion, proteolytic degradation of extracellular matrix and cell migration. Syk is a member of tyrosine kinase family that is mostly expressed in haematopoitic cells. Syk is expressed in the cell lines of epithelial origin, but its function in these cells remains unknown. Here we report that Syk is expressed in MCF-7 cells but not in MDA-MB-231 cells. The overexpression of wild type Syk kinase but not kinase negative Syk (SykK-) suppressed the cell motility and inhibited activation of PI 3'-kinase in MDA-MB-231 cells. In contrast, Syk specific antisense S-oligonucleotide (ASSyk) but not the sense S-oligonucleotide (SSyk) when transfected to the MCF-7 cells, the level of PI 3’-kinase activity as well as cell motility were increased. The MDA-MB-231 cells transfected with wild type Syk cDNA followed by treatment with piceatannol, a Syk inhibitor, enhanced the cell motility and PI 3’-kinase activity. Pervanadate (pV), a phosphotyrosine phosphatase inhibitor induced the PI 3’-kinase activity and stimulated the interaction between IkBa and p85a domain of PI 3’-kinase through tyrosine phosphorylation of IkBa which ultimately resulted in NF-kB activation. pV had no effect on activation of Syk in these cells. However, Syk suppressed the NF-kB transcriptional activation and interaction between IkBa and PI 3’-kinase by inhibiting the tyrosine phosphorylation of IkBa. Syk, PI 3’-kinase inhibitors and NF-kB inhibitory peptide (SN50) inhibited the uPA secretion and cell motility in these cells. To our knowledge, this is the first report that Syk suppresses the cell motility and inhibits the PI 3’-kinase activity and uPA secretion by blocking the NF-kB activity through tyrosine phosphorylation of IkBa. These data further demonstrate a functional molecular link between Syk regulated PI 3'-kinase activity and NF-kB mediated uPA secretion, all of these ultimately control the motility of breast cancer cells.
J. Biol. Chem, 10.1074/jbc.M208905200
Submitted on August 30, 2002
Revised on December 10, 2002
Accepted on December 10, 2002
SYK, a protein tyrosine kinase suppresses the cell motility and nuclear factor kB mediated secretion of urokinase type plasminogen activator by inhibiting the phosphatidylinositol 3'-kinase activity in breast cancer cells
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